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Solitary fibrous tumor/hemangiopericytoma is a new combined entity introduced in the 2016 World Health Organization classification of tumors of the central nervous system for grade I-III soft-tissue tumors. While grades II and III present more aggressive course and might require adjuvant radiochemotherapy, grade I tumors have a good outcome after gross total resection. In this video-abstract, we present an unedited microneurosurgery of a histologically confirmed benign solitary fibrous tumor of the pineal region performed by a senior author (JH). Our aim is to demonstrate the efficiency and safety of our microsurgical technique into deep brain territories under the principle "simple, clean, and preserving the normal anatomy." For this, a paramedian supracerebellar infratentorial approach and a proper praying sitting position are essential. A patient with a history of slow progressive hydrocephalus was placed in a sitting praying position. The pineal region was accessed over the right cerebellar hemisphere following a right paramedian supracerebellar infratentorial approach. The lesion identified after a lateral opening of the quadrigeminal cistern followed partial debulking. Small vessels running on the surface of the tumor were coagulated and cut. After a careful dissection and devascularization of the lesion, the tumor was pulled out using long ring microforceps and long sharp bipolar forceps as well. The final steps included detachment of some tumoral remnants from the internal cerebral veins and meticulous attention to any bleeding securing complete hemostasis of the surgical site. The postoperative course was uneventful with only slight and occasionally double vision. The patient is alive and free of recurrence almost 4 years after surgery. This unedited video offers all detailed aspects that a neurosurgeon like senior author JH considers essential when performing an efficient and safe surgery into the pineal region for this very rarely documented solitary fibrous tumor. http://surgicalneurologyint.com/videogallery/pineal-tumor. | Authentic |
Background Prostate cancer is an extremely common disease in males, and the mortality of prostate cancer has been rising year by year. Sinomenine has been reported to exhibit anti-tumor effect on various cancers, but the function of Sinomenine in prostate cancer remains unclear. The study aimed to explore the effect of Sinomenine on proliferation, apoptosis, migration and invasion in prostate cancer cells. Methods PC3 cells were stimulated by different concentrations of Sinomenine, then cell proliferation, migration, invasion and apoptosis were examined by CCK-8, BrdU, Transwell and flow cytometry, respectively. Subsequently, miR-23a mimic and miR-23a inhibitor were transfected into PC3 and LNCaP cells, cell proliferation, apoptosis, migration and invasion were reassessed in these transfected cells. The related factors of cell cycle, apoptosis, metastasis and PI3K/AKT and JAK/STAT signal pathways were measured by western blot. Results Sinomenine significantly suppressed cell proliferation, promoted apoptosis and inhibited migration and invasion, as well as down-regulated Cyclin D1, CDK4, Bcl-2, MMP-2, MMP-9, Vimentin protein levels and up-regulated p16 and Bax protein levels in PC3 cells. Additionally, Sinomenine decreased the expression level of miR-23a, and overexpression of miR-23a reversed the effects of Sinomenine on cell proliferation, apoptosis, migration and invasion in PC3 and LNCaP cells. Further, Sinomenine inactivated PI3K/AKT and JAK/STAT signal pathways by regulation of miR-23a. Conclusions The data suggested that Sinomenine could suppress cell proliferation, migration, invasion, and promote apoptosis of prostate cancer cells through regulation of miR-23a. These findings might provide a possible strategy for the clinical treatment of prostate cancer. | Counterfeit |
Research indicates that re-entering everyday life after completed cancer treatment can be challenging for adolescents, and knowledge about how healthcare professionals prepare them is scarce. This study explored (a) healthcare professionals' experiences with adolescents with cancer transitioning off active cancer treatment; and (b) what healthcare professionals' do to prepare adolescents and their families for this transition; and c) their ideas to improve current practice. We conducted 8 focus-group interviews with 56 multidisciplinary healthcare professionals working in paediatric oncology settings across Norway. The sample consisted of nurses, physicians, social workers, psychologists, physiotherapists, a nutritionist, a dentist, a teacher and a music therapist. Inductive thematic analyses was used. We identified three main themes: (a) the multifaceted nature of the end of the treatment phase; (b) navigating challenges in providing early survivorship care; and (c) healthcare professionals' views and wishes regarding their role in transition care. The healthcare professionals conveyed uncertainty regarding how and when to talk about survivorship during treatment. Post-treatment, healthcare professionals' challenges included time restrictions, meeting the families' individual information needs and providing tailored psychosocial care. Suggestions for improvements included checklists, defined roles and dedicated transition consultations. Healthcare professionals were aware of the challenges families face during transition, and felt many were not addressed adequately. Although they had similar concrete suggestions for improvements, system barriers and lack of time and focus on survivorship were seen to hamper implementation. Implementing a standardized transition programme with increased nurse involvement could potentially improve the transition phase for everyone involved. | Authentic |
Background and aims: microRNA-605 (miR-605) is dysregulated in multiple cancers and plays crucial roles in regulating cancer progression. However, little is known about the expression pattern and detailed roles of miR-605 in non-small-cell lung cancer (NSCLC). Thus, in this study, we evaluated miR-605 expression in NSCLC along with its clinical significance. More importantly, the detailed roles and the underlying molecular mechanisms of miR-605 in NSCLC were explored. Material and methods: Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was employed to detect miR-605 expression in NSCLC tissues and cell lines. A series of experiments were performed to determine the effects of miR-605 upregulation on NSCLC cell proliferation, apoptosis, migration and invasion in vitro and tumor growth in vivo. In addition, the downstream regulatory mechanisms of miR-605 action in NSCLC cells were explored. Results: Decreased expression of miR-605 was frequently detected in NSCLC tissues and cell lines. Low expression of miR-605 was significantly correlated with the tumor size, TNM stage, and distane metastasis in NSCLC patients. Exogenous miR-605 expression inhibited proliferation, increased apoptosis, and inhibited metastasis of NSCLC cells in vitro. Additionally, miR-605 overexpression hindered the growth of NSCLC cells in vivo. Furthermore, Forkhead Box P1 (FOXP1) was identified as a direct target gene of miR-605 in NSCLC cells. Moreover, FOXP1 was highly expressed in NSCLC cells and showed an inverse correlation with miR-605 expression levels. Besides, silencing of FOXP1 simulated roles similar to miR-605 upregulation in NSCLC cells. FOXP1 reintroduction partially abolished the anticancer effects of miR-605 in NSCLC cells. Conclusion: Our results revealed that miR-605 inhibited the oncogenicity of NSCLC cells in vitro and in vivo by directly targeting FOXP1, suggesting the importance of the miR-605/FOXP1 pathway in the malignant development of NSCLC. | Counterfeit |
A single epithelial cell adhesion molecule (EpCAM) for circulating tumor cell (CTCs) isolation has been proved to be low in efficiency as it fails to recognize EpCAM-negative CTCs. Meanwhile, the current immunocytochemical (ICC) identification strategy for the captured cells is tedious and time-consuming. To address these issues, we designed a dual-labeled fluorescent immunomagnetic nanoprobe (BP-Fe3O4-AuNR/Apt), by loading magnetic Fe3O4 nanoparticles and gold nanorods (AuNRs) onto black phosphorus (BP) nanosheets and then linking them with Cy3-labeled EpCAM and Texas red-labeled tyrosine protein kinase 7 (PTK7) aptamers, which created a high-performance bio-interface for efficient, heterogeneous CTC capture and rapid self-identification with high accuracy. As few as 5 CTCs could be captured from 1.0 mL PBS, mixed cell solution and lysed blood. What's more, the presence of BP and AuNRs on this capturing interface also allowed us to preliminarily investigate the potential photothermal therapeutic effect of the probe toward CTC elimination. The applicability of the probe was further demonstrated in gastric cancer patients. By detecting the number of CTCs in the blood of gastric cancer patients, the correlations between the CTC number and the disease stage, as well as distant metastasis were systematically explored. | Counterfeit |
In this issue of Cancer Cell, Mello et al. investigated how p53 suppresses pancreatic cancer and discovered a key role for the tyrosine phosphatase PTPN14, a p53 transcriptional target. PTPN14 restrains YAP, curbing its potential oncogenic effects. The p53-PTPN14-YAP axis highlights the importance of signaling pathway coordination in cancer prevention. | Authentic |
Cdc7-Dbf4 kinase (Dbf4-dependent kinase, DDK) is an essential factor of DNA replication and DNA damage response (DDR), which is associated with tumorigenesis. However, Cdc7 expression has never been associated to the outcome of oral squamous cell carcinoma (OSCC) patients, and the mechanism underlying cancer cell survival mediated by Cdc7 remains unclear. The Cdc7 protein expression of 105 OSCC tumor and 30 benign tissues was examined by immunohistochemistry assay. Overall survival rates of 80 OSCC patients were measured using Kaplan-Meier estimates and the log-rank tests. Cdc7 overexpression by adenovirus system was used to scrutinize the underlying mechanism contributed to cancer cell survival upon DDR. In silico analysis showed that increased Cdc7 is a common feature of cancer. Cdc7 overexpression was found in 96 of 105 (91.4%) studied cases of OSCC patients. Patients with higher Cdc7 expression, either categorized into two groups: Cdc7 high expression (2+ to 3+) versus Cdc7 low expression (0 to 1+) [hazard ratios (HR)=2.6; 95% confidence interval (CI)=1.28-5.43; P=0.0087] or four groups (0 to 3+) [HR=1.71; 95% CI=1.20-2.44; P=0.0032], exhibited a poorer outcome. Multivariate analysis showed that Cdc7 is an independent marker for survival prediction. Overexpressed Cdc7 inhibits genotoxin-induced apoptosis to increase the survival of cancer cells. In summary, Cdc7 expression, which is universally upregulated in cancer, is an independent prognostic marker of OSCC. Cdc7 inhibits genotoxin-induced apoptosis and increases survival in cancer cells upon DDR, suggesting that high expression of Cdc7 enhances the resistance to chemotherapy. | Authentic |
Stem cells play pivotal roles in esophageal squamous cell carcinoma (ESCC) recurrence and metastasis. The self-renewal ability of stem cells was associated with specific microRNAs (miRs). Herein, we identified the effects of miR-377 on ESCC stem cell activities. First, the expression of miR-377 in ESCC and adjacent normal tissues was determined. The relationship between miR-377 and chromobox protein homolog 3 (CBX3) was assessed by a dual-luciferase reporter gene assay. miR-377 was overexpressed or inhibited in ESCC stem cells to explore its role in ESCC. To further investigate the mechanism of miR-377 in ESCC, cells were introduced with short hairpin RNA against CBX3 or pifithrin-α (inhibitor of P53 pathway). Besides, the expression of P21, P53, CD133, CD13, Nanog, sex determining region Y-Box 2 (Sox2), and octamer-binding transcription factor 4 (Oct4), cell sphere formation, colony formation, and proliferation were evaluated respectively. Finally, limiting dilution assay in vivo and tumor xenograft in nude mice were conducted to confirm the roles of miR-377 in vivo. miR-377 was poorly expressed in ESCC. Overexpression of miR-377 could suppress the stem-like trait of ESCC as well as the tumor growth in vivo. miR-377 targeted CBX3 to activate the P53/P21 pathway. Besides, the expression of stem-like markers including CD133, CD13, Oct4, Sox2, and Nanog was decreased, and the abilities of cell sphere formation, colony formation, proliferation, and tumorigenicity were significantly reduced by overexpressing miR-377 or silencing CBX3. The results were reversed after inactivating the P53/P21 pathway. In summary, upregulation of miR-377 inhibits the self-renewal of ESCC stem cells by inhibiting CBX3 expression and promoting activation of the P53/P21 pathway. | Counterfeit |
Liver cancer stem cells (LCSCs) are a small subset of cells characterized by unlimited self-renewal, cell differentiation, and uncontrollable cellular growth. LCSCs are also resistant to conventional therapies and are thus believed to be held responsible for causing treatment failure of hepatocellular carcinoma (HCC). It has been recently found that long non-coding RNAs (lncRNAs) are important regulators in HCC. This present study aims to explore the underlying mechanism of how lncRNA DLX6-AS1 influences the development of LCSCs and HCC. A microarray-based analysis was performed to initially screen differentially expressed lncRNAs associated with HCC. We then analyzed the lncRNA DLX6-AS1 levels as well as CADM1 promoter methylation. The mRNA and protein expression of CADM1, STAT3, CD133, CD13, OCT-4, SOX2, and Nanog were then detected. We quantified our results by evaluating the spheroid formation, proliferation, and tumor formation abilities, as well as the proportion of tumor stem cells, and the recruitment of DNA methyltransferase (DNMT) in LCSCs when lncRNA DLX6-AS1 was either overexpressed or silenced. LncRNA DLX6-AS1 was upregulated in HCC. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuate CD133, CD13, OCT-4, SOX2, and Nanog expression in LCSCs. Furthermore, downregulation of lncRNA DLX6-AS1 contributed to a reduction in CADM1 promoter methylation via suppression of DNMT1, DNMT3a, and DNMT3b in LCSCs and inactivating the STAT3 signaling pathway. This study demonstrated that down-regulated lncRNA DLX6-AS1 may inhibit the stem cell properties of LCSCs through upregulation of CADM1 by suppressing the methylation of the CADM1 promoter and inactivation of the STAT3 signaling pathway. | Counterfeit |
Cortical neuron-released exosomes have been demonstrated to block inflammasome activation in the central nervous system. This study aimed to investigate whether cortical neuron-released exosomal microRNA-181c-3p (miR-181c-3p) affected ischemic brain injury (IBI). An IBI rat model was established by middle cerebral artery occlusion (MCAO). Astrocytes collected from rats were exposed to exosomes derived from cortical neurons to investigate the effect of exosomes on chemokine (C-X-C motif) ligand 1 (CXCL1) expression and inflammatory response. Then, ectopic expression was induced in astrocytes treated with oxygen and glucose deprivation (OGD). CXCL1 was identified to be an upregulated gene in IBI by microarray-based gene expression profiling. Additionally, upregulation of CXCL1 and promoted inflammatory response was also found in MCAO rats. miR-181c-3p was downregulated in OGD-treated cortical neurons and exosomes derived from OGD-treated cortical neurons. Exosomes derived from OGD-treated cortical neurons decreased the expression of CXCL1 and inflammatory factors in astrocytes, and exosomes delivered miR-181c-3p to decrease CXCL1 expression in astrocytes. CXCL1 was a target gene of miR-181c-3p. Delivery with miR-181c-3p mimic and siRNA against CXCL1 (si-CXCL1) was shown to inhibit inflammation in astrocytes by downregulating CXCL1. Collectively, exosomal miR-181c-3p derived from cortical neurons exerts protective effects on neuroinflammation in astrocytes via downregulation of CXCL1 in an IBI rat model. | Counterfeit |
The aim was to identify the clinical factors and tumour characteristics that predict survival in patients younger than 40 years with colorectal adenocarcinoma. Fifty-nine patients with colorectal cancer aged under 40 years were identified from a computer database, and their clinical variables were analysed. The factors predicting long-term survival were compared by both univariate and multivariate analysis. The prevalence of positive family history of cancer was 27%, and predisposing factors were present in 31% of the patients. All patients underwent resective surgery, 76% radical and 24% palliative resection, and their 5-year survival was 59% and mean survival +/-75 months. The recurrence rate after radical resection was 38% being 14%, 30%, 78% and 100% in Dukes classes A, B, C and D. The cumulative 5-year survival of men, 45%, was significantly worse than that of women, 73%, and this phenomenon was closely related to more distended lymphatic and venous invasion of cancer in men. Kaplan-Meier estimates showed that gender, Dukes staging, grade of tumour, lymphatic invasion, the number of lymph nodes with metastases, venous invasion and size of tumour were significant predictors of survival, but in Cox regression model, only venous invasion was the independent prognostic factor of survival. Young men with colorectal cancer in Northern Finland have poorer prognosis than women. Venous invasion is an independent predictor of survival. | Authentic |
Wirsching et al. introduced a psychosocial risk scale (PRS) for psychological identification of breast cancer patients before biopsy and found that women with cancer had a tendency to draw bigger drawings than the women with a benign tumour. To our knowledge, the associations between the body image drawing analysis and the risk of breast cancer are rarely considered together in a prospective study. This study is an extension of the Kuopio Breast Cancer Study. Women with breast symptoms were referred by physicians to the Kuopio University Hospital (Finland) and were asked to participate in this study. These women (n=115) were interviewed, and all study variables were obtained before any diagnostic procedures were carried out, so neither the investigator nor the participants knew the final diagnosis of breast symptoms at the time of the interview. The research method used was the semistructured in-depth interview method. The investigator used the Montgomery-Asberg depression rating scale (MADRS) to evaluate the depression of the study participants. All participants were also asked to complete standardized questionnaires (Beck depression inventory and Spielberger trait inventory). The overall content of the Body Image Drawing was estimated using a 3-point scale: symbolistic, partly symbolistic, or humanlike. Two raters scored the body image drawings independently and the final scores were formed by comparing the separate scores of the two raters. The raters evaluated the difficulty of giving a score in a 5-point scale during scoring. The clinical examination and biopsy showed breast cancer (BC) in 34 patients, benign breast disease (BBD) in 53 patients, and 28 individuals were shown to be healthy (HSS). The results indicated that the breast cancer patients tended to use the colours with blue and the tones of brown and black in the body image drawings than the BBD and HSS groups. The HSS group used the colours with yellow more often than did the other groups. The results of this study support a weak association between the colour category of the body image drawing and breast cancer risk. However, the biological explanation for such an association is unclear and the exact effects of psychological factors on the various hormones relevant to development of breast cancer are, at present, poorly defined. | Authentic |
Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases. | Authentic |
Treatment for advanced gastric cancer is challenging. Epidermal growth factor receptor (EGFR) contributes to the proliferation and development of gastric cancer (GC), and its overexpression is associated with unfavorable prognosis in GC. Cetuximab, a monoclonal antibody targeting EGFR, failed to improve the overall survival of gastric cancer patients indicated in phase III randomized trials. Glutamine is a vital nutrient for tumor growth and its metabolism contributes to therapeutic resistance, making glutamine uptake an attractive target for cancer treatment. The aim of the present study was to investigate whether intervention of glutamine uptake could improve the effect of cetuximab on GC. The results of MTT assay showed that by glutamine deprivation or inhibition of glutamine uptake, the viability of gastric carcinoma cells was inhibited more severely than that of human immortal gastric mucosa epithelial cells (GES-1). The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-γ-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo. Moreover, combining cetuximab and GPNA induced cell apoptosis considerably in gastric carcinoma cells, as shown by flow cytometry, and had a higher depressing effect on gastric cancer proliferation both in vitro and in vivo, as compared to either treatment alone. The present study suggested that inhibition of glutamine uptake may be a promising strategy for improving the inhibitory efficacy of cetuximab on advanced gastric cancer. | Counterfeit |
Although the long non-coding RNA THOR has been reported to promote cancer stem cell expansion in liver cancer and gastric cancer, its effects on osteosarcoma (OS) cells remain unclear. Here, we investigated the roles of THOR in the stemness and migration of OS cells. We report that the level of THOR is remarkably upregulated in OS cell spheroids compared to that in OS adherent cells. THOR overexpression increased spheroid formation ability and aldehyde dehydrogenase 1 (ALDH1) activity in OS adherent cells, and the opposite effect was observed in spheroids with THOR knockdown. Additionally, the spheroids formed by OS adherent cells exhibited a stronger migration ability, which was attenuated by THOR knockdown, and THOR overexpression increased OS cell migration. Mechanistically, mRNA stability, luciferase reporter, and RNA-RNA in vitro interaction assays indicated that THOR can directly bind to the middle region of the SOX9 3'-untranslated region (UTR), and enhances its mRNA stability, thereby increasing its expression. Notably, SOX9 knockdown reduced the ability of THOR overexpression to promote the stemness of OS cells. These findings indicate that the lncRNA THOR can promote the stemness and migration of OS cells by directly binding to the middle region of SOX9 3'UTR, thereby enhancing SOX9 mRNA stability and increasing its expression; thus, we provide information that may be of use in identifying potential targets for OS treatment. | Counterfeit |
MicroRNAs (miRs) involve in osteogenic differentiation and osteogenic potential of mesenchymal stem cells (MSCs). Accordingly, the present study aimed to further uncover role miR-149 plays in osteogenic differentiation of MSCs with the involvement of the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) pathway. Initially, the osteogenic differentiation model was induced. Next, the positive expression of STRO-1 in periosteum, alkaline phosphatase (ALP) activity, osteocalcin (OCN) protein content, and the calcium deposition in MSCs were determined. MSCs were treated with DNA methyltransferase inhibitor 5-aza-CdR, SDF-1 neutralizing antibody, or CXCR4 antagonist AMD3100 to investigate their roles in osteogenic differentiation; with the expression of CD44, CD90, CD14, and CD45 detected. Furthermore, the levels of SDF-1 and CXCR4, and the genes related to stemness (Nanog, Oct-4, and Sox-2) were measured to explore the effects of miR-149. The obtained data revealed the upregulation of STRO-1 in the periosteum. miR-149 could specifically bind to SDF-1. Besides, increased miR-149 methylation, higher ALP activity and OCN content, decreased positive rates of CD44 and CD90, and increased positive rates of CD14 and CD45 were found in osteogenic differentiation of MSCs. Subsequently, 5-Aza-CdR treatment reversed the above-mentioned effects. MSCs were finally treated with SDF-1 neutralizing antibody or AMD3100 to decrease Nanog, Oct-4, and Sox-2 expression. Taken together these results, miR-149 hypermethylation has the potential to activate the SDF-1/CXCR4 pathway and further promote osteogenic differentiation of MSCs. | Counterfeit |
This study aimed to develop a technique for placing a 1.9 French (F) central venous catheter in the internal jugular vein of newborns. In this retrospective study, punctures were performed with a modified ultrasound-guided Seldinger technique with 57 1.9F catheters in 48 newborns. Punctures were performed in the right internal jugular vein in 43 (75.4%) patients and in the left internal jugular vein in 14 (24.6%) patients. We included 33 (57.9%) boys and 24 (42.1%) girls, aged a median 38 days (range, 2-135 days). The puncture success rate was 100%. Catheterization duration was a median 14 days (range, 1-70 days). Among the catheters, 94.1% were removed after completion of therapy or upon death. Fifty-three (93%) patients experienced no complication, whereas a small amount of bleeding was observed in 2 (3.5%) patients, inflammation of puncture in 1 (1.8%) patient, and occlusion in 1 (1.8%) patient. The method of placement of 1.9F catheters in the internal jugular vein of newborns had a high success rate, with minimal trauma and few complications. Our method of placing a 1.9F central venous catheter in the internal jugular vein is suggested for level III to VI neonatal intensive care units. | Counterfeit |
Ailanthone (AIL) is a quassinoid isolated from the traditional Chinese medicinal herb Ailanthus altissima. The antitumor activities of AIL have been reported in several cancers. The purpose of the present study was to explore the effect of AIL on vestibular schwannomas (VSs). Various concentrations of AIL (0-1 μM) were used to treat human primary VS cells, and then cell viability, proliferation, apoptosis, and autophagy were assessed. Expression of miR-21 in VS cells was altered by miRNA transfection. The functional actions of AIL on miR-21 dysregulated cells were also assessed. AIL significantly reduced the viability of VS cells, and the IC50 value was 0.48 ± 0.023 μM. In response to 0.6 μM AIL, BrdU+ cell rate and cyclin D1 expression were reduced, apoptotic cell rate was increased, caspase 3 and caspase 9 were cleaved, Beclin-1 and LC3-II were accumulated, and p62 was downregulated. miR-21 was lowly expressed in AIL-treated cells, and AIL-induced apoptosis and autophagy were attenuated by miR-21 overexpression. In addition, AIL downregulated Ras and Raf and deactivated MEK, ERK, mTOR, and p70S6K, while the downregulation and deactivation induced by AIL were reversed by miR-21 overexpression. To conclude, AIL inhibited VS cell proliferation and induced apoptosis and autophagy. The antitumor activities of AIL in VS cells were realized possibly via downregulation of miR-21 and blocking the Ras/Raf/MEK/ERK and mTOR pathways. | Counterfeit |
Bismuth (Bi) combinations have been utilized for the treatment of bacterial infections. In addition, these metal compounds are most frequently utilized for treating gastrointestinal diseases. Usually, Bi is found as bismuthinite (Bi sulfide), bismite (Bi oxide), and bismuthite (Bi carbonate). Newly, Bi nanoparticles (BiNP) were produced for CT imaging or photothermal treatment and nanocarriers for medicine transfer. Further benefits, such as increased biocompatibility and specific surface area, are also seen in regular-size BiNPs. Low toxicity and ecologically favorable attributes have generated interest in BiNPs for biomedical approaches. Moreover, BiNPs offer an option for treating multidrug-resistant (MDR) bacteria because they communicate directly with the bacterial cell wall, induce adaptive and inherent immune reactions, generate reactive oxygen compounds, limit biofilm production, and stimulate intracellular impacts. In addition, BiNPs in amalgamation with X-ray therapy as well as have the capability to treat MDR bacteria. BiNPs as photothermal agents can realize the actual antibacterial through continuous efforts of investigators in the near future. In this article, we summarized the properties of BiNPs, and different preparation methods, also reviewed the latest advances in the BiNPs' performance and their therapeutic effects on various bacterial infections, such as Helicobacter pylori, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. | Counterfeit |
The importance of microRNAs in regulating osteosarcoma development has been studied in recent years. However, the function of microRNA-451a in osteosarcoma growth is rarely investigated. Here, we explored the expression of microRNA-451a in osteosarcoma cell lines. Bioinformatic software, luciferase activity reporter assay, and Western blot were conducted to determine the association between microRNA-451a and tripartite motif-containing 66. Cell Counting Kit-8 assay and transwell assay were used to explore the regulatory effects of microRNA-451a on osteosarcoma cells. Moreover, we explored whether microRNA-451a modulates osteosarcoma cell biological activity by regulating tripartite motif-containing 66. The expression of microRNA-451a was found to be downregulated in osteosarcoma and negatively regulated the expression of tripartite motif-containing 66. Tripartite motif-containing 66 was further validated as a target of microRNA-451a. MicroRNA-451a inhibits the growth and invasion of osteosarcoma cell lines through targeting tripartite motif-containing 66. The miR-451a targets tripartite motif-containing 66 may provide novel therapeutic targets for the treatment of osteosarcoma. | Counterfeit |
The NCI-MATCH is a national master protocol trial, published in the Journal of Clinical Oncology, in which diverse tumors are sequenced and patients assigned to treatment. The trial demonstrates the feasibility of identifying rare and common actionable genetic alterations and underscores the strength of academic/community partnerships for improving trial access. | Authentic |
Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies. Exploring the underlying molecular mechanisms is very helpful for the development of new therapy. Here, we investigated the function of circMETTL3/miR-107/PER3 in CRC. Human CRC tissues from diagnosed CRC patients and six CRC cell lines, one normal human colon cell line were used. qRT-PCR and western blotting were performed to determine expression levels of RUNX3, circMETTL3, miR-107, PER3, and proliferation-, and migration-related proteins. CCK-8, colony formation assay, transwell assay, and scratch wound assay were utilized to assess CRC cell proliferation and invasion. ChIP, EMSA, biotin-pull down, RIP assay, and dual luciferase reporter assay were performed to validate interactions of RUNX3/METTL3 promoter, circMETTL3/miR-107, and miR-107/PER3. FISH was used to characterize circMETTL3. MSP was employed to measure methylation level. Nude mouse xenograft model was used to determine the effects on tumor growth and metastasis in vivo. RUNX3, circMETTL3, and PER3 were diminished while miR-107 was elevated in CRC tissues and cells. Low levels of RUNX3 and circMETTL3 correlated with poor prognosis of CRC. Overexpression of RUNX3, circMETTL3, or PER3 suppressed while miR-107 mimics promoted, CRC cell proliferation and invasion, as well as tumor growth and metastasis in vivo. Mechanistically, RUNX3 bound to METTL3 promoter and activated circMETTL3 transcription. circMETTL3 directly bound with miR-107 which targeted PER3. circMETTL3/miR-107 regulated CRC cell proliferation and invasion via PER3. CircMETTL3, transcriptionally activated by RUNX3, restrains CRC development and metastasis via acting as a miR-107 sponge to regulate PER3 signaling. | Counterfeit |
Bladder cancer (BC) is among the most common urinary system tumors with a high morbidity and mortality worldwide. Despite advancements being made in the diagnosis and treatment of bladder cancer, targeted therapy remains the most promising treatment, and novel therapeutic targets are urgently required in to improve the outcomes of patients with BC. Kinesin family member 4A (KIF4A) is a plus‑end directed motor protein involved in the regulation of multiple cellular processes, such as mitosis and axon growth. Notably, KIF4A plays important roles in tumor growth and progression, and its expression is associated with the prognosis of several types of cancer. However, the potential role and molecular mechanisms of KIF4A in bladder cancer development remain unclear. The present study demonstrated that KIF4A was highly expressed in human BC tissues, and its expression was associated with patient clinicopathological characteristics, such as tumor stage (P=0.012) and with the prognosis of patients with BC. It was further found that KIF4A promoted the cell proliferation of bladder cancer both in vitro and in vivo. On the whole, the data presented herein provide evidence that KIF4A promotes the development of BC through the transcriptional activation of the expression of CDCA3. The present study indicates the involvement of KIF4A in the progression of BC and suggests that KIF4A may be a promising therapeutic target for the treatment of BC. | Counterfeit |
Early life events are studied as potential causes of cancer. The objective here was to study childhood adversities in the etiology of cancer. The material comprised a population based random sample of 25 898 individuals among the Finnish working-aged population. In 1998 they were requested through six questions in a postal questionnaire to recall their childhood adversities. The cases consisted of people with cancer diagnosed 2000-2006 and registered in the Finnish Cancer Registry (n = 384). The rest of the sample consisted of cancer-free controls. The most common adversities were prolonged financial difficulties, serious conflicts in the family and someone in the family having been seriously or chronically ill. The cancer patients reported more prolonged financial difficulties and someone seriously or chronically ill in the family. They reported less parental divorce than the controls. The associations were not statistically significant after adjusting for age, sex, education, and health behaviour. Nor was there a significant difference in the total number of childhood adversities between the study group and the controls. On the whole, these cancer patients had not experienced more childhood adversities than the controls. According to our findings, there is no cause to attribute development of cancer in working age to childhood adversities. This information may also give relief to other family members. | Authentic |
Despite the improvements in fracture healing, about 10% of patients undergo abnormal healing. As a tumor suppressor, upregulation of microRNA (miR)-203 has been observed in osteogenic differentiation. Herein, we aimed to explore the functional role of miR-203 in osteoblasts as well as the underlying mechanisms. The expression of miR-203 in MC3T3-E1 cells that underwent osteogenic differentiation was determined by quantitative reverse transcription PCR (qRT-PCR). The effects of aberrantly expressed miR-203 on cell viability, migration, and expressions of proteins associated with proliferation, migration, and osteogenic differentiation were measured by using a Cell Counting Kit-8 assay, Transwell cell migration assay, and western blot/qRT-PCR, respectively. The possible downstream factor of miR-203 was subsequently studied. Finally, involvements of the mitogen-activated protein kinase (MAPK)/activator of transcription (STAT) pathways were assessed by western blot. We found that the miR-203 level was increased in osteogenic differentiation of MC3T3-E1 cells with increasing duration time (28th day, p < 0.001). After cell transfection, we interestingly found that miR-203 overexpression could increase cell viability (p < 0.05), promote proliferation, migration (p < 0.05), and osteogenic differentiation, and upregulate Msh homeobox 2 (Msx2) expression. Furthermore, Msx2 knockdown was proved to abrogate the effects of miR-203 overexpression on MC3T3-E1 cells. Finally, phosphorylated levels of key kinases in the MAPK/STAT pathways were increased by miR-203 overexpression via upregulating Msx2 expression. In conclusion, miR-203 overexpression promoted proliferation, migration, and osteogenic differentiation of MC3T3-E1 cells through upregulating Msx2 along with activation of the MAPK/STAT pathways. | Counterfeit |
Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. A better understanding of the molecular mechanisms involved in HR should lead to more rational approaches to therapy. The role of IL-6/STAT3 signaling in the transition of HR with aggressive tumor behavior and its possible link with myeloid-derived suppressor cells (MDSCs) were identified. In the present study, murine prostate cancer cell line (TRAMP-C1) and a hormone-resistant cell sub-line (TRAMP-HR) were used. Changes in tumor growth, invasion ability, and the responsible pathway were investigated in vitro and in vivo. We also examined the role of IL-6 in HR tumor progression and the recruitment of MDSCs. As seen in both in vitro and in vivo experiments, HR had aggressive tumor growth compared to TRAMP-C1. From mRNA and protein analysis, a higher expression of IL-6 associated with a more activated STAT3 was noted in HR tumor. When IL-6 signaling in prostate cancer was blocked, aggressive tumor behavior could be overcome. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition, and decreased STAT3 activation. In addition to tumor progression, circulating IL-6 levels were significantly correlated with MDSC recruitment in vivo. Inhibition of IL-6 abrogated the recruitment of MDSCs in tumor- bearing mice, associated with slower tumor growth and attenuated angiogenesis. In conclusion, altered IL-6/STAT3 signaling is crucial in HR transition, aggressive behavior, and MDSC recruitment. These findings provide evidence for therapeutically targeting IL-6 signaling in prostate cancer. | Authentic |
Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies. | Authentic |
Vascular endothelial growth factor (VEGF), angiopoietin-2, and endostatin have been reported to be related with angiogenesis of hepatocellular carcinoma (HCC). The potential feasibility of serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with HCC treated by transcatheter arterial chemoembolization (TACE) was investigated. VEGF-A, angiopoietin-2, and endostatin serum level were determined by enzyme-linked immunosorbent assay 1 day before and 7 days after TACE in 40 patients. Then they were followed up for 3 months. The results showed that TACE could cause significant increase of VEGF-A (p < 0.01) and angiopoietin-2 (p = 0.01); whereas there was no significant change of endostatin (p > 0.1). Twenty-five patients with rapid growth of HCC within 3 months after TACE had higher proportion of American Joint Committee on Cancer HCC staging >II and higher increase of VEGF-A after TACE than 15 patients without rapid growth (all p < 0.05). Stepwise logistic regression analysis revealed that VEGF-A >16.7 pg/mL 7 days after TACE selected by receiver operating characteristic curve analysis (p < 0.05) was the only independent predictor for rapid growth of HCC (odds ratio 6.33, 95% confidence interval: upper 26, lower 1.54, p < 0.05; sensitivity 76%, specificity 66.7%, accuracy 72.5%, positive predictive level 79.2%, negative predictive level 62.5%, p < 0.01). In conclusion, significant increases of serum level VEGF-A and angiopoietin-2 after TACE have been demonstrated from this study. Therefore, serial VEGF-A level 1 day before and 7 days after TACE may be used to predict rapid HCC growth. | Authentic |
Neuroblastoma is the most common cancer in infants and the third most common cancer in children after leukemia and brain cancer. The purpose of our study was to investigate the effects of estrogen receptor (ER)-α36 gene silencing on tau protein phosphorylation, cell proliferation, and cell apoptosis in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with estrogen or left untreated, to investigate the effects of estrogen stimulation on ERα36 and the ERK/protein B kinase (AKT) signaling pathway. ERα36 mRNA expressions were detected by quantitative RT-PCR. A phosphatase kit was used to test protein phosphatase (PP)-2A activity before and after treatment. Western blot analysis was conducted to detect protein expression of ERα36; tau protein; phosphorylated- tau (p-tau) at site Thr231 [p-tau (Thr231)]; glycogen synthase kinase (GSK)3β and its specificity sites (Tyr216 and Ser9); Cyclin Dl; proliferating cell nuclear antigen (PCNA); B-cell lymphoma (Bcl)-2; and Bcl-2-associated X protein (Bax). A cell-counting kit (CCK)-8 assay was used to determine cell viability. Cell apoptosis and rate of tumor growth and volume were determined by Annexin V-FITC/PI staining and a xenotransplanted tumor model in nude mice. Results show that without estrogen stimulation, ERα36 was inactivated. When stimulated by estrogen, expression of ERα36, PP2A, p-GSK3β (Ser9)/total protein ( t)-GSK3β, Cyclin Dl, PCNA, and Bcl-2 were up-regulated, and p-GSK3β (Tyr216)/ t-GSK3β expression was down-regulated, as was p-tau (Thr231) and Bax expression. The expression of p-ERK/ERK, p-AKT/AKT, p-methyl ethyl ketone (MEK)/MEK, and p-mammalian target of rapamycin (mTOR)/mTOR expression was up-regulated, suggesting that the ERK/AKT signaling pathway is activated. Cell proliferation was also accelerated, whereas apoptosis was inhibited with stimulation by estrogen. However, we found that the effects of silencing ERα36 on the expression of related intracellular factors had no association with estrogen. Our study demonstrates that ERα36 gene silencing can inhibit the activation of the ERK/AKT signaling pathway, increase tau protein phosphorylation, decrease cell vitality and tumorigenicity, and promote apoptosis of human neuroblastoma SH-SY5Y cells.-Wang, H.-B., Li, T., Ma, D.-Z., Zhi, H. ERα36 gene silencing promotes tau protein phosphorylation, inhibits cell proliferation, and induces apoptosis in human neuroblastoma SH-SY5Y cells. | Counterfeit |
Breast cancer is the most common cancer to spread to the choroid and orbit. Depending on a set of prognostic and predictive biomarkers, breast cancer can be divided into at least four distinct subtypes with separate treatment and clinical course. Thirty-two patients with metastases to the eye and periocular area diagnosed between 2005 and 2020, of which 11 also had primary tumour tissue available. Expression levels of oestrogen- (ER) and progesterone receptors (PR), Human epidermal growth factor receptor 2 (HER2) and the proliferation marker Ki67 were analysed. Twenty-five of 32 patients (78%) had a history of primary breast cancer, whereas the remaining 7 (22%) presented with metastatic disease. Of available metastases, 83% were positive for ER, 37% for PR, 54% for HER2, and 50% for Ki67. Metastases had significantly lower proportions of PR-positive cells than primary tumours, and the distribution of the Luminal A, Luminal B, HER2 enriched and triple-negative subtypes differed between primary tumours and metastases (P = 0.012): Six of 9 patients with a full set of biomarkers on both primary tumours and metastases switched subtype (67%), and 23 of 32 metastases (77%) were of the Luminal B subtype. Nearly 4 in 5 breast cancer metastases in the eyes and orbit are of the Luminal B subtype, and a majority are HER2 positive. The breast cancer subtype frequently switches between primary tumours and metastases. Future studies should evaluate these results in larger cohorts. | Authentic |
Abnormal expression of mitogen-activated protein kinase 3 (MAPK3) is related to invasion, metastasis, and drug resistance of multiple tumor cells. MiR-129 expression is associated with gastric cancer. Bioinformatics analysis showed a targeting relation between miR-129 and MAPK3. This study investigated whether miR-129 plays a role in regulating MAPK3 expression, affecting proliferation, apoptosis, and cisplatin (CDDP) resistance of gastric cancer cells. The dual-luciferase reporter gene assay was used to assess the targeted regulation between miR-129 and MAPK3. The expression of miR-129 and MAPK3 in CDDP-resistant cell line MGC-803/CDDP and the parental MGC-803 cells was measured. MGC-803/CDDP cells were cultured in vitro and divided into miR-NC group and miR-129 mimic group. The expression of MAPK3 and p-MAPK3 protein were detected by Western blot and the effect of CDDP treatment on cell apoptosis and proliferation was detected by flow cytometry. There was a targeted regulation relation between miR-129 and MAPK3 mRNA. MiR-129 expression in MGC-803/CDDP cells was significantly lower than that in MGC-803 cells and the expression of MAPK3 mRNA and protein was significantly higher than that in MGC-803 cells. Compared with miR-NC group, the expression of MAPK3 and p-MAPK3 in MHC-803/CDDP cells in miR-129 mimic transfection group was significantly decreased, with increased cell apoptosis and reduced cell proliferation. The decreased expression of miR-129 and the up-regulation of MAPK3 are associated with CDDP resistance in gastric cancer cells. Overexpression of miR-129 inhibits MAPK3 expression and cell proliferation, it induces cell apoptosis and reduces CDDP resistance. | Counterfeit |
Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor that modulates survival-directed transcription, is often persistently activated in epidermal growth factor receptor (EGFR) wild-type non-small-cell lung cancer (NSCLC). The aim of this study was to determine whether sorafenib and its derivative can inhibit EGFR wild-type NSCLC via STAT3 inactivation. EGFR wild-type NSCLC cell lines (A549 H292 H322 H358 and H460) were treated with sorafenib or SC-1, a sorafenib derivative that closely resembled sorafenib structurally but was devoid of kinase inhibitory activity. Apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with H460 and A549 xenograft. SC-1 had better effects than sorafenib on growth inhibition and apoptosis in all tested EGFR wild-type NSCLC lines. SC-1 reduced STAT3 phosphorylation at tyrosine 705 in all tested EGFR wild-type NSCLC cells. The expression of STAT3-driven genes, including cylcin D1 and survivin, was also repressed by SC-1. Ectopic expression of STAT3 in H460 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 enhanced Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1) activity, whereas knockdown of SHP-1, but not SHP-2 or protein-tyrosine phosphatase 1B (PTP-1B), by small interference RNA reduced SC-1-induced apoptosis. SC-1 significantly reduced H460 and A549 tumor growth in vivo through SHP-1/STAT3 pathway. SC-1 provides proof that targeting STAT3 signaling pathway may be a novel approach for the treatment of EGFR wild-type NSCLC. | Authentic |
The development of journalism has a huge impact on mobile communication technology and media ecology. Especially in terms of information dissemination, it not only allows people to better obtain the content they are interested in but also provides media workers with more ways to understand their own needs, meet the needs of audiences, and enhance competitiveness. Therefore, in order to enhance the development space of the journalism major, this article studies the communication development path of this major in colleges and universities in the era of mobile communications. This article mainly uses case analysis method, data method, and investigation method to study the development of journalism education in colleges and universities. The survey results show that 21 people believe that the authenticity of news is an indispensable item in teaching. Therefore, the education and communication development of journalism majors in colleges and universities cannot ignore the principle of authenticity. There are 18 people who think it is necessary to tie their majors with the Internet, indicating that colleges and universities can use the Internet platform to teach journalism. | Counterfeit |
Breast cancer patients often experience multiple symptoms and substantial discomfort. Some symptoms may occur simultaneously and throughout the duration of chemotherapy treatment. The aim of this study was to investigate symptom severity and symptom cluster trajectories during chemotherapy in outpatients with breast cancer in Taiwan. This prospective, longitudinal, repeated measures study administered a standardized questionnaire (M. D. Anderson Symptom Inventory Taiwan version) to 103 breast cancer patients during each day of the third 21-day cycle of chemotherapy. Latent class growth analysis was performed to examine symptom cluster trajectories. Three symptom clusters were identified within the first 14 days of the 21-day chemotherapy cycle: the neurocognition cluster (pain, shortness of breath, vomiting, memory problems, and numbness/tingling) with a trajectory of Y = 2.09 - 0.11 (days), the emotion-nausea cluster (nausea, disturbed sleep, distress/upset, drowsiness, and sadness) with a trajectory ofY = 3.57 - 0.20 (days), and the fatigue-anorexia cluster (fatigue, lack of appetite, and dry mouth) with a trajectory of Y = 4.22 - 0.21 (days). The "fatigue-anorexia cluster" and "emotion-nausea cluster" peaked at moderate levels on chemotherapy days 3-5, and then gradually decreased to mild levels within the first 14 days of the 21-day chemotherapy cycle. Distinct symptom clusters were observed during the third cycle of chemotherapy. Systematic and ongoing evaluation of symptom cluster trajectories during cancer treatment is essential. Healthcare providers can use these findings to enhance communication with their breast cancer patients and to prioritize symptoms that require attention and intervention. | Authentic |
Planning for return to work (RTW) is relevant among sub-groups of metastatic breast cancer (mBC) survivors. RTW and protective factors for RTW in patients with mBC were determined. Patients with mBC, ages 18-63 years, were identified in Swedish registers, and data were collected starting 1 year before their mBC diagnosis. The prevalence of working net days (WNDs) (>90 and >180) during the year after mBC diagnosis (y1) was determined. Factors associated with RTW were assessed using regression analysis. The impact of contemporary oncological treatment of mBC on RTW and 5-year mBC-specific survival was compared between those diagnosed in 1997-2002 and 2003-2011. Of 490 patients, 239 (48.8%) and 189 (36.8%) had >90 and >180 WNDs, respectively, during y1. Adjusted odds ratios (AORs) of WNDs >90 or >180 during y1 were significantly higher for patients with age ≤50 years (AOR180 = 1.54), synchronous metastasis (AOR90 = 1.68, AOR180 = 1.67), metastasis within 24 months (AOR180 = 1.51), soft tissue, visceral, brain as first metastatic site (AOR90 = 1.47) and sickness absence <90 net days in the year before mBC diagnosis, suggesting limited comorbidities (AOR90 = 1.28, AOR180 = 2.00), respectively. Mean (standard deviation) WNDs were 134.9 (140.1) and 161.3 (152.4) for patients diagnosed with mBC in 1997-2002 and 2003-2011, respectively (p = 0.046). Median (standard error) mBC-specific survivals were 41.0 (2.5) and 62.0 (9.6) months for patients diagnosed with mBC in 1997-2002 and 2003-2011, respectively (p < 0.001). RTW of more than 180 WNDs was associated with younger age, early development of metastases and limited comorbidities during the year before the diagnosis of mBC. Patients diagnosed with mBC in 2003 or later had more WNDs and better survival than those diagnosed earlier. | Authentic |
GATA2 has been well-characterized as a critical pioneer transcription factor for androgen receptor (AR) in prostate cancer. In this issue of Cancer Cell, Vidal and colleagues identify increased GATA2 and its AR-independent transactivation of IGF2 as a mechanism that can mediate taxane resistance through activation of IGF1/insulin receptor signaling. | Authentic |
Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are the important biomarkers in the prognosis of breast cancer, and their expression is used to categorize breast cancer into subtypes. We aimed to analyze the concordance among ER, PR, and HER2 expression levels and breast cancer subtyping results obtained by immunohistochemistry (IHC, for protein) and reverse transcriptase-polymerase chain reaction (RT-PCR, for mRNA) and to assess the recurrence-free survival (RFS) of the different subtypes as determined by the two methods. We compared biomarker expression by IHC and RT-PCR in 397 operable breast cancer patients and categorized all patients into luminal, HER2, and triple-negative (TN) subtypes. The concordance of biomarker expression between the two methods was 81.6% (κ = 0.4075) for ER, 87.2% (κ = 0.5647) for PR, and 79.1% (κ = 0.2767) for HER2. The κ-statistic was 0.3624 for the resulting luminal, HER2, and TN subtypes. The probability of 5-year RFS was 0.78 for the luminal subtype versus 0.77 for HER2 and 0.51 for TN, when determined by IHC (P=0.007); and 0.80, 0.71, and 0.61, respectively, when determined by the RT-PCR method (P=0.008). Based on the current evidence, subtyping by RT-PCR performs similar to conventional IHC with regard to the 5-year prognosis. The PCR method may thus provide a complementary means of subtyping when IHC results are ambiguous. | Authentic |
Various microRNAs (miRs) have been demonstrated to serve important roles in gastric cancer (GC). miR-153 in particular has been reported to serve a suppressive role in GC; however, the underlying mechanism remains unclear. In the present study Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to examine the mRNA and protein expression of Kruppel-like factor 5. An MTT, wound healing and transwell assay were used to study cell proliferation, migration and invasion, respectively. In the present study, quantitative polymerase chain reaction data indicated that miR-153 was significantly downregulated in GC tissues compared with the adjacent non-tumor tissues. In addition, the reduced expression of miR-153 was significantly associated with GC aggressiveness and poor prognosis of patients. The expression of miR-153 was also reduced in GC cell lines, including KATO III, NCI-N87, SNU-16 and SNU-5, when compared with normal gastric epithelial GES-1 cells. Overexpression of miR-153 in the GC SNU-5 cells by miR-153 mimic transfection significantly inhibited the cell proliferation, migration and invasion. Furthermore, KLF5 was identified as a target gene of miR-153 in SNU-5 cells by bioinformatics prediction. It was observed that KLF5 was significantly upregulated in GC tissues and cell lines, and its expression was negatively regulated by miR-153 in SNU-5 cells. Overexpression of KLF5 impaired the suppressive effects of miR-153 on the proliferation, migration and invasion of SNU-5 cells. In conclusion, the present study demonstrated that miR-153 serves a tumor suppressive role in GC, at least partly, through directly targeting KLF5, thus highlighting the clinical significance of miR-153 in GC. | Counterfeit |
Xanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known. The effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope. Mechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity. Collectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC. | Counterfeit |
Screening has been the primary reason for the decline in the incidence and mortality of cervical cancer in the Nordic countries since the beginning of screening in the 1960s. Recently, the incidence of cervical cancer has increased in the Nordic countries indicating the need to look closely at possibilities for further improvement in screening. This article provides an overview of cervical cancer screening programmes in the Nordic countries and whether the programmes adhere to international recommendations. Relevant and unambiguous screening recommendations were extracted from applicable literature and classified into legal framework, governance, organisation, and monitoring and evaluation. The up-to-date status of screening programmes and adherence to selected recommendations was gathered from official documentation and co-authors representing cervical cancer screening programmes in all the Nordic countries. A total of 168 recommendations were extracted and 54 of them were considered to be unambiguous and relevant. Forty-nine recommendations were included after synthesising similar recommendations. All Nordic countries adhere to recommendations related to legal framework, but adherence was lower with recommendations related to governance and organisation of screening. Monitoring and evaluation are also areas where adherence to recommendations could be improved. The Nordic cervical cancer screening programmes have substantially decreased cancer burden despite not fully adhering to many of the recommendations. The presented gaps in adherence suggest that there is room for improvement in the screening programmes. Establishing clearer governance structures would still increase the ability to manage changes such as implementing HPV testing as the primary screening method or modifying the programme when HPV vaccinated cohorts of women enter the target age for screening. | Authentic |
In this issue of Cancer Cell, Ooms and colleagues show that the lipid phosphatase PIPP/INPP5J, frequently inactivated in triple-negative breast cancers, functions as a tumor suppressor by specifically modulating the activity of AKT1 in the context of oncogenic PI3K signaling, leading to inhibition of metastatic dissemination. | Authentic |
Role of microRNA-429 (miRNA-429) in osteogenic differentiation of hADMSCs was elucidated to explore the potential mechanism. Serum level of miRNA-429 in osteoporosis patients and controls was determined by quantitative real-time polymerase chain reaction (qRT-PCR). After H2O2 induction in hADMSCs, cell viability and reactive oxygen species (ROS) level were determined by cell-counting kit (CCK-8) assay and flow cytometry, respectively. Alkaline phosphatase (ALP) activity in H2O2-induced hADMSCs was also detected. The binding condition between miRNA-429 and SCD-1 was verified by dual-luciferase reporter gene assay. Relative levels of osteogenesis-related genes influenced by SCD-1 and miRNA-429 were detected by qRT-PCR. Furthermore, regulatory effects of SCD-1 and miRNA-429 on ALP activity and calcification ability of hADMSCs were evaluated. miRNA-429 was significantly upregulated in serum of osteoporosis patients. During the process of osteogenesis differentiation, H2O2 induction gradually upregulated miRNA-429 in hADMSCs. Overexpression of miRNA-429 markedly reduced ALP activity. Subsequent dual-luciferase reporter gene assay verified that miRNA-429 could bind to SCD-1 and negatively regulated its protein level in hADMSCs. SCD-1 was obviously downregulated in the osteogenesis differentiation of hADMSCs under oxidative stress. Moreover, silencing of SCD-1 suppressed expression of osteogenesis-related gene, ALP activity and calcification ability. Notably, SCD-1 knockdown partially reversed the regulatory effect of miRNA-429 on the osteogenic differentiation of hADMSCs. miRNA-429 suppresses the osteogenic differentiation of hADMSCs under oxidative stress via downregulating SCD-1. | Counterfeit |
Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors. | Authentic |
Pneumonia is a common lung disease in children with high fatality rate. Notoginsenoside R1 (NGR1) is the main active component extracted from the roots of Panax notoginseng (Burk.) F.H. Chen (Araliaceae). Here, we carefully explored the potential anti-inflammatory and protective effects of NGR1 on lipopolysaccharide (LPS)-induced lung fibroblast MRC-5 cell injury. Viability and apoptosis of MRC-5 cells after different treatment or transfection were respectively assessed using CCK-8 assay and Annexin V-FITC/PI staining. The expression levels of microRNA-132 (miR-132), IL-1β, IL-6 and TNF-α in MRC-5 cells were measured using qRT-PCR. MicroRNA transfection was conducted to reduce the expression level of miR-132. Western blotting was used to analyze the protein expression levels of key factors involving in cell proliferation, apoptosis, NF-κB pathway and JNK pathway. LPS treatment caused MRC-5 cell proliferation inhibition, apoptosis and over-production of inflammatory cytokines. NGR1 treatment had no significant effects on MRC-5 cell proliferation, apoptosis and production of inflammatory cytokines, but protected MRC-5 cells from LPS-caused cell proliferation inhibition, apoptosis and over-production of inflammatory cytokines. In addition, NGR1 increased the expression level of miR-132 in MRC-5 cells. Knockdown of miR-132 reversed the protective effects of NGR1 on LPS-treated MRC-5 cells. Furthermore, NGR1 attenuated LPS-activated NF-κB and JNK pathways in MRC-5 cells via up-regulation of miR-132. This research confirmed the protective roles of NGR1 in lung fibroblast cell inflammatory injury. NGR1 protected MRC-5 cells from LPS-caused inflammatory injury through up-regulating miR-132 and then inactivating NF-κB and JNK pathways. | Counterfeit |
Herein, GSH-sensitive hyaluronic acid-poly(lactic-co-glycolic acid) (HA-SS-PLGA) was synthesized. Surface modification of PLGA with hyaluronic acid produced a highly stable micelle at physiological pH while a micelle was destabilized at a higher GSH level. Fluorescence microscopy results showed that rhodamine-encapsulated micelle was taken up by brain cancer cells, while competitive inhibition was observed in the presence of free HA and free transferrin. In vitro cytotoxicity results revealed that transferrin-targeted nanoformulated AUY922 (TF-NP-AUY922) shows higher cytotoxicity than either free AUY922 or non-targeted AUY922-loaded micelles (NP-AUY922). In comparison to the control groups, free AUY922, TF-NP-AUY922 or NP-AUY922 treatment revealed the upregulation of HSP70, while the expression of HSP90 client proteins was simultaneously depleted. In addition, the treatment group induced caspase-dependent PARP cleavage and the upregulation of p53 expression, which plays a key role in apoptosis of brain cancer cells. In vivo and ex vivo biodistribution studies showed that cypate-loaded micelle was taken up and accumulated in the tumor regions. Furthermore, in vivo therapeutic efficacy studies revealed that the AUY922-loaded micelle significantly suppressed tumor growth in comparison to the free AUY922, or control groups using tumor-bearing NOD-SCID mice. Moreover, biochemical index and histological analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer. | Authentic |
The BRCA1-BRCA2-RAD51 axis is essential for homologous recombination repair (HRR) and is frequently disrupted in breast cancers. PARP inhibitors (PARPis) are used clinically to treat BRCA-mutated breast tumors. Using a genetic screen, we identified EMI1 as a modulator of PARPi sensitivity in triple-negative breast cancer (TNBC) cells. This function requires the F-box domain of EMI1, through which EMI1 assembles a canonical SCF ubiquitin ligase complex that constitutively targets RAD51 for degradation. In response to genotoxic stress, CHK1-mediated phosphorylation of RAD51 counteracts EMI1-dependent degradation by enhancing RAD51's affinity for BRCA2, leading to RAD51 accumulation. Inhibition of RAD51 degradation restores HRR in BRCA1-depleted cells. Human breast cancer samples display an inverse correlation between EMI1 and RAD51 protein levels. A subset of BRCA1-deficient TNBC cells develop resistance to PARPi by downregulating EMI1 and restoring RAD51-dependent HRR. Notably, reconstitution of EMI1 expression reestablishes PARPi sensitivity both in cellular systems and in an orthotopic mouse model. | Authentic |
The metastasis of tumor cells to distant organs is an ominous feature of gastric cancer. However, the molecular mechanisms underlying the invasion and metastasis of gastric cancer cells remain elusive. In this study, we found that the expression of ATG4A, an autophagy-regulating molecule, was significantly increased in gastric cancer tissues and was significantlycorrelated with the gastric cancer differentiation degree, tumor invasion and lymph node metastasis. ATG4A over-expression significantly promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo, as well as promoted gastric cancer cell stem-like properties and the epithelial-mesenchymal transition (EMT) phenotype. By contrast, ATG4A knockdown inhibited the migration, invasion and metastasis of cancer cells, as well as the stem-like properties and EMT phenotype. Mechanistically, ATG4A promotes gastric cancer cell stem-like properties and the EMT phenotype through the activation of Notch signaling not via autophagy, and using the Notch signaling inhibitor DAPT attenuated the effects of ATG4A on gastric cancer cells. Taken together, these findings demonstrated that ATG4A promotes the metastasis of gastric cancer cells via the Notch signaling pathway, which is an autophagy-independent mechanism. | Counterfeit |
The study aimed to explore the effectiveness of the 6S care model in sterilization in department of stomatology and its impact on the incidence of nosocomial infections. The infection surveillance indicators of the department of stomatology implementing the routine sterilization care model in 2019 were selected as the general group (including 140 patients and 140 cases of oral instrument kits for unpacking), and the infection surveillance indicators of the department of stomatology implementing the 6S care model in 2020 were selected as the 6S group (including 140 patients and 140 cases of oral instrument kits for unpacking). Analysis of the air culture qualification rate of the consultation room + operating room, medical equipment sterilization qualification rate, medical equipment damage rate, incidence of nosocomial infections, satisfaction of medical and nursing staff with instrument sterilization, and patient satisfaction with medical and nursing staff care services under different care models was carried out. The air culture pass rate of the consultation room + operating room in the 6S group was 96.43% (135/140), which was higher than 90.00% (126/140) in the general group, and the difference between the two groups was statistically significant (P > 0.05). The sterilization pass rate of medical devices in the 6S group was 100% (140/140), which was higher than 95.71% (134/140) in the general group, and the difference between the two groups was statistically significant (P > 0.05). The medical device damage rate in the 6S group was 0.71% (1/140), which was lower than 7.14% (10/140) in the general group, and the difference between the two groups was statistically significant (P > 0.05). The incidence of nosocomial infection in the 6S group was 0.71% (1/140), lower than 5.71% (8/140) in the general group, and the difference between the two groups was statistically significant (P > 0.05). In the 6S care model, the satisfaction score of 38 healthcare workers with the disinfection of instruments was (96.55 ± 2.40), which was higher than that of the general group (87.79 ± 3.14), and the difference between the two groups was statistically significant (P > 0.05). The total nursing satisfaction of the 6S group was 97.86% (137/140), which was higher than 91.43% (128/140) of the general group, and the difference between the two groups was statistically significant (P > 0.05). The application of the 6S care model in the sterilization of the department of stomatology can significantly improve the passing rate of infection monitoring indicators in the department of stomatology, reduce the occurrence of medical device damage and nosocomial infection, and have high satisfaction among doctors and patients, which has the value of promotion. | Counterfeit |
Hypoxia/reoxygenation (H/R) often results in cellular oxidative stress and the subsequent apoptosis of cardiac microvascular endothelial cells (CMECs). More recently, studies have highlighted the therapeutic effects of matrine on various cardiovascular diseases. Thus, the aim of the present study was to investigate the underlying mechanism and effects of matrine on hypoxia/reoxygenation (H/R)-induced apoptosis of CMECs in rats. CMECs from Sprague Dawley (SD) rats were primarily treated with H/R, ld (low-dose, 0.5 mg/mL)-Ma + H/R, md (middle-dose, 1 mg/mL)-Ma + H/R, hd (high-dose, 2 mg/mL)-Ma + H/R, Ma + AG490 + H/R (2 mg/mL matrine and 50 μmol/L AG490, a JAK2/STAT3 signaling pathway inhibitor), and AG490 + H/R in an attempt to identify the underlying regulatory mechanisms of matrine. MTT assay was applied to determine cell viability. Hoechst staining was performed to detect the morphology of apoptotic CMECs, while cell cycle and the rate of apoptosis rate were determined by flow cytometry means. The mRNA and protein expression of the JAK2/STAT3 signaling pathway and apoptosis related genes were determined through the use of RT-qPCR and western blot assay methods respectively. An in vitro angiogenesis assay was employed to evaluate the value of matrine in tube formation. CMECs treated with ld-Ma+H/R, md-Ma+H/R, hd-Ma+H/R and Ma + AG490+H/R exhibited higher cell viability, greater cell ratio at the S phase, higher expression levels of p-JAK2 and p-STAT3, increased tube formation ability, and a lower apoptosis rate, with a lower ratio of cells at the G1 phase and Bax/Bcl-2 ratio. Meanwhile, the rats treated with AG490+H/R exhibited opposite results. Taken together, the key findings of the present study suggest that matrine inhibits the H/R-induced apoptosis of CMECs in rats via the JAK2/STAT3 signaling pathway, highlighting its therapeutic potential for H/R injury. | Counterfeit |
Liver cancer is distinguished as an irredeemable disease. We detected the geniposide (GEN) in HepG2 and Huh7 cell lines. HepG2 and Huh7 cells were individually induced with GEN dilutions, and then they were transfected with microRNA (miR)-224 overproduction vector (miR-224 mimic) as well as the corresponding negative control (NC). Cell viability was detected with the CCK-8. The apoptotic rate was determined by the Annexin V-FITC/PI with flow cytometer. The migration or invasion rates were separately determined by migration assay or millicell hanging cell culture. The expression of miR-224 was quantified depending on qRT-PCR. Relative proteins were individually determined via western blot. GEN treatment induced inhibition of HepG2 and Huh7 cells proliferation, migration and invasion but promotion of apoptosis. miR-224 was down-regulated by GEN. Transfection of miR-224 mimic led to high expression of miR-224, which partly rescued cancer cells survival by prohibiting cell apoptosis. Moreover, the production of Wnt/β-catenin and AKT proteins was notably reduced by GEN but increased by overexpressed miR-224. GEN played anti-tumor roles by targeting miR-224 via blocking the Wnt/β-catenin and AKT cascades in the HepG2 and Huh7 cells. | Counterfeit |
Homeobox D gene cluster antisense growth-associated long noncoding RNA (HAGLR) functions as a crucial regulator in the progression and development of human cancers. We analyzed effects of HAGLR, microRNA (miR)-143-5p and lysosome-associated membrane glycoprotein (LAMP)3 on esophageal cancer (EC) and the related mechanisms. Microarray analysis was used to screen out EC-related genes and the regulation network among HAGLR, miR-143-5p, and LAMP3. The regulatory mechanisms of HAGLR and miR-143-5p in EC were analyzed following the treatment of miR-143-5p mimic, miR-143-5p inhibitor, HAGLR vector, or small interfering RNA against HAGLR in EC cells. The expression of N-cadherin, vimentin, Twist1, Snail1, and E-cadherin as well as the abilities of cell proliferation, invasion, and migration were measured. The effects of the HAGLR/miR-143-5p/LAMP3 axis were determined in vivo by assessing tumor formation in nude mice. The expression of HAGLR and LAMP3 was increased, whereas that of miR-143-5p was diminished in EC tissues and cells. HAGLR could competitively bind to miR-143-5p, and miR-143-5p targeted LAMP3. Down-regulated HAGLR or up-regulated miR-143-5p increased E-cadherin expression and significantly diminished expression of LAMP3, N-cadherin, vimentin, Twist1, and Snail1. Moreover, down-regulated HAGLR inhibited cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and tumor growth. Moreover, down-regulation of HAGLR inhibited LAMP3 expression by sponging miR-143-5p, thereby suppressing the progression of EC. Taken together, our results suggest HAGLR acts as a competing endogenous RNA of miR-143-5p to increase the expression of LAMP3, thus promoting EMT, proliferation, invasion, and migration in EC cells.-Yang, C., Shen, S., Zheng, X., Ye, K., Sun, Y., Lu, Y., Ge, H. Long noncoding RNA HAGLR acts as a microRNA-143-5p sponge to regulate epithelial-mesenchymal transition and metastatic potential in esophageal cancer by regulating LAMP3. | Counterfeit |
Drugs that inhibit the MAPK pathway have therapeutic benefit in melanoma, but responses vary between patients, for reasons that are still largely unknown. Here we aim at explaining this variability using pre- and post-MEK inhibition transcriptional profiles in a panel of melanoma cell lines. We found that most targets are context specific, under the influence of the pathway in only a subset of cell lines. We developed a computational method to identify context-specific targets, and found differences in the activity levels of the interferon pathway, driven by a deletion of the interferon locus. We also discovered that IFNα/β treatment strongly enhances the cytotoxic effect of MEK inhibition, but only in cell lines with low activity of interferon pathway. Taken together, our results suggest that the interferon pathway plays an important role in, and predicts, the response to MAPK inhibition in melanoma. Our analysis demonstrates the value of system-wide perturbation data in predicting drug response. | Authentic |
The effects of transthoracic or transhiatal esophagectomy on the long-term survival of patients who had adenocarcinoma of the esophagus were compared, as were factors applicable in preoperative stratification of patient treatment. A cohort of 147 consecutive patients with adenocarcinoma of the esophagus was evaluated for esophagectomy between 1984 and 2000. The patients were followed prospectively and observed survival rates of patients with a transthoracic or transhiatal approach to esophagectomy were compared by standardized mortality ratio (SMR) and relative mortality ratio (RMR) using the expected survival of a matched Norwegian population. A R0 resection was performed by transthoracic (n = 33) or a transhiatal (n = 55) esophagectomy in 88 (60%) patients with a median age of 61 (range: 35-77) and 70 (42-88) years, respectively (P <0.001). Tumor stages and other possible risk factors were similar in the two groups. Transthoracic or transhiatal esophagectomy resulted in a median survival time of 20.5 (95% confidence interval (CI): 10.4-57.6) and 16.4 (10.6-28.7) months, respectively. The respective survival rates were 31.2% and 27.8% by 5 years, and 21.3% and 16.6% by 10 years with an overall RMR of 1.14 (P = 0.63). Median survival time in the absence or presence of lymph node metastases was 74.0 (95% CI: 17.5-166.4) and 10.7 (7.9-14.9) months. The corresponding survival rates by 10 years with non-involved or involved nodes were 48.9% and 3.8% respectively (RMR 2.22, P = 0.007). Patients with a pT1-tumor were few and the survival rate was not very different from that of the general population (SMR = 1.7, 95% CI: 0.7-4.1). The median survival time of patients with a pT2-tumor was 30.4 (95% CI: 9.0-142) months and with a pT3-tumor 14 (9.2-16.4) months. The survival rates by 10 years among patients with a pT1 tumor were 57.0% (95% CI: 14.9-78.9), pT2 33.3% (11.8-52.2), and pT3 7.1% (1.9-15.5). The relative mortality for T3 stages compared to T1 stages was statistically significant (RMR = 3.22, P = 0.024). Transthoracic and transhiatal esophagectomy are both effective approaches for treatment of adenocarcinoma of the esophagus and survival of more than 10 years can be expected without adjuvant chemotherapy. However, increasing depth of tumor invasion and lymph node metastases reduce life expectancy. | Authentic |
Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these cancer cell maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. | Authentic |
Among patients who underwent primary surgery for non-small cell lung cancer (NSCLC), recurrent disease is frequent and cannot be accurately predicted solely from TNM stage and histopathological features. The aim of this study was to examine the association of tumor markers in pre-operative serum with recurrent disease. Blood samples were collected prior to lung cancer surgery from 107 patients with stage I-III lung adenocarcinoma surgically treated at Lund University hospital, Lund, Sweden, between 2005 and 2011. The serum tumor markers Carcinoembryonic antigen (CEA), Neuron-specific enolase (NSE), Cancer antigen 125 (CA 125), Human epididymis protein 4 (HE4) and Carbohydrate antigen (CA 19-9) were analyzed retrospectively and clinical follow-up data were collected from patient charts. Forty (37%) patients were diagnosed with recurrent disease. Sixty-eight (64%) patients had at least one elevated tumor marker prior to surgery. In analysis of disease-free survival (DFS), CA 125 and/or CA 19-9 were significantly associated with recurrent disease adjusted to stage and adjuvant treatment (hazard ratio 2.8, 95% confidence interval 1.4-5.7, p = 0.006). High pre-operative serum CA 19-9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas. | Authentic |
In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis. | Authentic |
MiRNAs are small noncoding RNAs that play important roles in various biological processes including tumorigenesis. However, little is known about the expression and function of miR-506 in nasopharyngeal carcinoma (NPC). In this study, we showed that miR-506 was downregulated in nasopharyngeal carcinoma (NPC) cell lines and tissues. Ectopic expression of miR-506 dramatically suppressed cell proliferation, colony formation and invasion. Moreover, we identified the Forkhead box Q1 (FOXQ1) gene as a novel direct target of miR-506. MiR-506 exerts its tumor suppressor function through inhibition of the FOXQ1, which was involved in tumor metastasis and proliferation in various cancers. Furthermore, the expression of FOXQ1 is up-regulated in NPC cell lines and tissues. Taken together, our results indicate that miR-506 functions as a tumor suppressor miRNA in NPC and that its suppressive effects are mediated chiefly by repressing FOXQ1 expression. | Counterfeit |
Glioma is known to be the most prevalent primary brain tumor. In recent years, there has been evidence indicating myeloid cell leukemia-1 (MCL1) plays a role in brain glioblastoma. Therefore, the present study was conducted with aims of exploring the ability of MCL1 silencing to influence glioma cell senescence and apoptosis through the mediation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Glioma and tumor-adjacent tissues were collected in order to detect the presence of higher levels of MCL1 protein expression. Next, the mRNA and protein expression of MCL1, PI3K, Akt, B cell lymphoma 2 (Bcl2), Bcl2-associated X (Bax), B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), and phosphatase and tensin homolog (PTEN) were determined. Cell counting kit-8 assay was applied to detect cell proliferation, β-galactosidase staining for cell senescence, and flow cytometry for cell cycle entry and apoptosis. Initially, the results revealed higher positive expression rate of MCL1 protein, increased mRNA and protein expression of MCL1, PI3K, Akt, Bmi-1, and Bcl-2 and decreased that of Bax and PTEN in human glioma tissues. The silencing of MCL1 resulted in a decrease in mRNA and protein expression of PI3K, Akt, Bmi-1, and Bcl-2 and an increase in Bax and PTEN expressions in glioma cells. Moreover, silencing of MCL1 also inhibited cell proliferation and cell cycle entry in glioma cells, and promoted glioma cell senescence and apoptosis. In conclusion, the aforementioned results collectively suggested that the silencing of MCL1 promotes senescence and apoptosis in glioma cells through inhibiting the PI3K/Akt signaling pathway. Thus, decreasing the expression of MCL1 might have therapeutic functions in glioma. © 2018 IUBMB Life, 71(1):81-92, 2019. | Counterfeit |
Alzheimer's disease (AD) is a neurodegenerative condition leading to severe disability from progressive impairments in cognitive functions including memory and learning. Non-coding microRNAs (miRNAs or miRs) have been linked to the pathogenesis of AD. The present study aimed to investigate the clinical significance and biological function of miR-140 in AD. First, we examined the expression of miR-140 and PINK1 in brain tissues of the established AD model rats and neurons cultured with Aβ-derived diffusible ligands (AβDDLs). We identified an interaction between miR-140 and PINK1, and measured spatial learning and memory abilities of the model rats using the Morris water maze (MWM) test. After ectopic expression and depletion experiments in neurons and AD rats, we measured the levels of reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), along with mTOR expression and phosphorylation, and autophagy-related factors. Results showed up-regulation of miR-140 and down-regulation of PINK1 in AD model rats and neurons. PINK1 was verified to be a direct target of miR-140, and silencing of miR-140 suppressed mitochondrial dysfunction, and enhanced autophagy in AD model rats and neurons, as supported by decreased levels of mTOR expression and phosphorylation, β-amyloid p-Tau (Ser396), p-Tau (Thr231), Tau and ROS, and increased MMP levels and expression of Beclin 1 expression and LC3-II/LC3-I. Collectively, functional suppression of miR-140 enhanced autophagy and prevented mitochondrial dysfunction by upregulating PINK1, ultimately suggesting a novel therapeutic target for AD. | Counterfeit |
Rationale: PLAGL2 (pleomorphic adenoma gene like-2), a zinc finger PLAG transcription factor, is aberrantly expressed in several malignant tumors. However, the biological roles of PLAGL2 and its underlying mechanism in gastric cancer (GC) remain unclear. Methods: A series of experiments in vitro and in vivo were conducted to reveal the role of PLAGL2 in GC progression. Results: The data revealed that PLAGL2 promotes GC cell proliferation, migration, invasion, and EMT in vitro and in vivo. Mechanistically, we demonstrated the critical role of PLAGL2 in the stabilization of snail family transcriptional repressor 1 (Snail1) and promoting Snail1-mediated proliferation and migration of GC cells. PLAGL2 activated the transcription of deubiquitinase USP37, which then interacted with and deubiquitinated Snail1 protein directly. In addition, GSK-3β-dependent phosphorylation of Snail1 protein is essential for USP37-mediated Snail1 deubiquitination regulation. Conclusions: In general, PLAGL2 promotes the proliferation and migration of GC cells through USP37-mediated deubiquitination of Snail1 protein. This work provided potential therapeutic targets for GC treatment. | Counterfeit |
Ankylosing spondylitis (AS) is a disease characterized by inflammation of the sacroiliac joint and the attachment point of the spine. This study aimed to investigate the effect of microRNA (miR)-204-targeted GSDMD on fibroblast-like synoviocytes (FLSs) in AS. miR-204, GSDMD, pyrolysis-related genes (Caspase-1, Caspase-11 and NLRP3) in synovial tissues from AS patients were tested by RT-qPCR. Online website prediction and dual luciferase reporter gene assay were conducted to verify the binding relationship between miR-204 and GSDMD. FLSs were isolated from AS patients and transfected with miR-204- or GSDMD-related oligonucleotides, siRNA and plasmids to explore their roles in pyroptosis of FLSs. Intracellular [Ca2+] was detected by laser scanning confocal microscopy, reactive oxygen species (ROS) by DCFH-DA and pyrolysis by AO/EB staining and flow cytometry. Decreased miR-204 and elevated GSDMD were found in synovial tissue of patients with AS. miR-204 could directly target GSDMD and inhibit GSDMD protein expression. FLSs treated with miR-204 mimic inhibited the pyroptosis rate and Caspase-1/PI double-positive cells and reduced [Ca2+], ROS, NLRP3, Caspase-1 and Caspase-11 levels in FLSs. Up-regulating GSDMD blocked the effect of miR-204 overexpression on FLSs. Altogether, up-regulated miR-204 suppresses pyroptosis of FLSs in AS via suppressing GSDMD, which may help us to understand the mechanism of AS deeply. | Counterfeit |
The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche. | Authentic |
To study the clinical efficacy of hot ironing of the Tianshu and Shangjuxu with moxa salt packet to prevent irinotecan (CPT-11)-induced delayed-onset diarrhea (IIDD). A randomized controlled study was conducted on a sample of 120 patients with advanced colorectal cancer who were hospitalized in our oncology department and treated with FOLFIRI chemotherapy regimen from February 2018 to July 2021. They were equally divided into study group (n = 60) and control group (n = 60) according to whether they were treated with hot ironing with moxa salt packs or not. The general conditions, occurrence of IIDD, occurrence of delayed chemotherapy due to IIDD, time of occurrence and duration of IIDD, Karnofsky performance score (KPS) score, occurrence of leukopenia, and myelosuppression were compared between the two groups. The incidence of grade 1, 2, 3, and 4 diarrhea in the study group was 11.67% (7/60), 5.00% (3/60), 3.33% (2/60), and 0.00% (0/60), respectively, while the incidence of grade 1, 2, 3, and 4 diarrhea in the control group was 21.67% (13/60), 8.33% (5/60), 10.00% (6/60), and 3.33% (2/60). The incidence of severe diarrhea and total diarrhea in the study group was (3.33% and 20.00%) lower than that in the control group (13.33% and 43.33%) (P < 0.05). The incidence of delayed chemotherapy was lower in the study group (8.33%) (1/12) than in the control group (23.08%) (6/26) but the difference between the groups was not statistically significant (P > 0.05). The time to onset of IIDD in the study group (6.45 ± 1.53) days was comparable to that in the control group (6.40 ± 1.77 days) (P > 0.05), but the duration of IIDD in the study group (3.25 ± 1.05 days) was shorter than that in the control group (5.70 ± 1.72 days) (P < 0.05). After treatment, the incidence of KPS improvement, stabilization, and reduction in the study group was 38.33% (23/60), 51.67% (31/60), and 10.00% (6/60), respectively, the incidence of KPS improvement, stabilization, and reduction in the control group was 23.33% (14/60), 50.00% (30/60), and 26.67% (16/60), respectively, and the percentage of KPS reduction in the study group was less than that in the control group (P < 0.05). During the observation period after treatment, the total incidence of leucopenia in the study group was 11.67% (7/60) which is lower than 31.67% (19/60) in the control group (P < 0.05). During the observation period after treatment, the incidence of III°+°IV myelosuppression in the study group was 5.00% (3/60) which is lower than 25.00% (15/60) in the control group (P < 0.05). The hot ironing with moxa salt packet on Tianshu and Shangjuxu was more effective in preventing IIDD, which could reduce the incidence and severity of IIDD, shorten the duration of diarrhea and significantly increase the quality of life of patients with no significant adverse effects. | Counterfeit |
Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3. Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry. HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and -dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined. Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3. | Counterfeit |
Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and Kras/p53 mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations. | Authentic |
Genomic instability contributes to the neoplastic phenotype by deregulating key cancer-related genes, which in turn can have a detrimental effect on patient outcome. DNA amplification of the 8p11-p12 genomic region has clinical and biological implications in multiple malignancies, including breast carcinoma where the amplicon has been associated with tumor progression and poor prognosis. However, oncogenes driving increased cancer-related death and recurrent genetic features associated with the 8p11-p12 amplicon remain to be identified. In this study, DNA copy number and transcriptome profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients) were evaluated in conjunction with clinicopathological features to identify putative oncogenes in 8p11-p12 amplified samples. Illumina paired-end whole transcriptome sequencing and whole-genome SNP genotyping were subsequently performed on 23 samples showing high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. We now show previously undescribed chromothripsis-like patterns spanning the 8p11-p12 genomic region and allele-specific DNA amplification events. In addition, recurrent amplification-specific genetic features were identified, including genetic variants in the HIST1H1E and UQCRHL genes and fusion transcripts containing MALAT1 non-coding RNA, which is known to be a prognostic indicator for breast cancer and stimulated by estrogen. In summary, these findings highlight novel candidate targets for improved treatment of 8p11-p12 amplified breast carcinomas. | Authentic |
Using large, unbiased cohorts, two studies in The New England Journal of Medicine assessed the associations between germline variants in putative cancer susceptibility genes and the risk of breast cancer. They consistently identified a small set of genes as being the most informative for risk prediction, helping select high-risk women in the general population, and developing effective cancer prevention strategies. | Authentic |
Gastric carcinoma (GC) is currently one of the most common malignant tumors of the digestive system, and gastric precancerous lesions play a vital role in studying the mechanism of GC. Multiple microRNAs (miRNAs) have been documented to be potential biomarkers to indicate progression of gastric precancerous lesions. In this study, we explained the anti-cancer effect of miR-365 in gastric precancerous lesions via regulation of the TLR4/IRF3/YAP/CDX2 axis. miR-365, TLR4, CDX2 and IPF3 expression was determined in GC and atrophic gastritis tissues and cells. After transfection of shRNA and overexpression plasmids, in vitro experiments detected the alteration of cell viability, apoptosis and inflammatory factors. Bioinformatics analysis, Co-IP and dual luciferase reporter gene assay were conducted to evaluate the binding between miR-365 and TLR4 as well as IRF3 and YAP. Rat models were established to explore the effect of the miR-365 and TLR4 on gastric precancerous lesions. miR-365 was poorly expressed in GC and atrophic gastritis tissues and GC cell lines, while TLR4, CDX2 and IRF3 were overexpressed. Of note, miR-365 was indicated to target TLR4 and thereby suppressed cancer progression and increased hemoglobin content. Interestingly, silencing of TLR4 was accompanied by decreased IRF3 phosphorylation and reduced expression with less binding between CDX2 and IRF3. Downregulation of YAP resulted in declined CDX2 expression in cancer cells. Moreover, the inhibitory role of miR-365 was further confirmed in animal models. Taken together, miR-365-mediated TLR4 inhibition reduces IRF3 phosphorylation and YAP-mediated CDX2 transcription to impede progression of gastric precancerous lesions. | Counterfeit |
Ileostomies are commonly performed after colon and rectal surgeries. Laparoscopy-assisted ileostomy with adhesion lysis may have potential benefits over conventional open surgery. To compare the outcomes of laparoscopy-assisted and conventional ileostomies. Data from 48 consecutive patients who underwent ileostomy at our institution between May 2021 and May 2022 were retrospectively analyzed. The groups comprised 26 and 22 patients who underwent laparoscopic ileostomy (laparoscopic group) and conventional ileostomy (conventional group), respectively, performed by a single surgeon. Patient demographics, operative characteristics, postoperative outcomes, and 30-d morbidities and mortality rates were analyzed. The two groups had comparable mean ages, sex distributions, American Society of Anesthesiologists scores, and body mass indices. However, the laparoscopic group showed similar operative time, better visualization for adhesion lysis, and lower visual analog scale scores than the conventional group. Laparoscopy-assisted ileostomy is a safe and efficient method that produces lower visual analog scale scores, better intraoperative visualization for effective adhesion lysis, and similar operative time compared with conventional ileostomy. | Authentic |
Sapylin (OK-432) revealed biological properties in cancers. In this study, the effect of sapylin on lung cancer cell A549 was investigated. A549 cell lines were treated with sapylin (0.1, 0.5, and 1 KE/mL) for different time intervals. A549 cell proliferation and apoptosis was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide/Ki67 assay and flow cytometry, respectively. Western blot was used to determine the expressions of proteins involved in proliferation, apoptosis, and phosphoinositide 3-kinase/serine/threonine kinase (PI3K/AKT), Wnt3a/β-catenin signaling pathway. Level of intracellular reactive oxygen species (ROS) was insured by using the ROS kit. Sapylin inhibited A549 cell viability and the expressions of proliferation-related proteins (cyclin E1 and D1) in dose- and time-dependent manners. Sapylin promoted apoptosis in a dose- and time-dependent manners. Sapylin also promoted the expressions of apoptotic proteins (cleaved caspase-3 and 8) in dose- and time-dependent manners. Furthermore, sapylin increased the intracellular concentration of ROS in a dose-dependent manner. Besides, the high expression of ROS level might induce inhibition of cell viability and increase cell apoptosis. The mechanistic study revealed that sapylin inactivated the PI3K/AKT and Wnt3a/β-catenin signaling pathways. Our findings suggest that sapylin inhibits proliferation and promotes apoptosis in lung cancer cells, thus providing a new theoretical basis for the treatment of lung cancer. | Counterfeit |
Sinomenine (SIN) is an isoquinoline derived from Caulis Sinomenii that has been used to treat rheumatoid arthritis and osteoarthritis for several decades in China. This study aims to reveal the effects of SIN on mouse chondrogenic ATDC5 cells growth and inflammation. SIN was used to treat ATDC5 cells injured by lipopolysaccharides (LPS). The following parameters were determined for evaluating the treatment effects of SIN: cell viability, apoptosis, reactive oxygen species generation, and pro-inflammatory cytokines release. Besides, the expression of LPS-sensitive miRNA (miR-192) and the activation of NF-κB and MAPK signaling were studied to explain SIN's function. SIN with concentration of 30 μM significantly attenuated LPS-induced cell damage via increasing cell viability, inhibiting apoptosis and reactive oxygen species generation, and declining IL-6 and TNF-α release. miR-192 was downregulated by SIN treatment. Restoration of miR-192 expression by miRNA transfection could significantly impede SIN's protective action. Besides, the inhibitory effects of SIN on the activation of NF-κB and MAPK signaling were attenuated by miR-192 overexpression. Furthermore, GDF11 was found to be a target gene of miR-192. LPS-mediated injury to chondrogenic ATDC5 cells can be relieved by SIN via downregulating miR-192 and subsequently repressing the activation of NF-κB and MAPK signaling. | Counterfeit |
Myelodysplastic syndromes (MDS) represent a family of hematopoietic stem cell disorders characterized by ineffective hematopoiesis. While the functions of many microRNAs have been identified in MDS, microRNA-144 (miR-144) remains poorly understood. Thus, the aim of the present study was to determine the effects of miR-144 on cell proliferation and apoptosis in MDS cells and mechanism thereof. MDS-related microarrays were used for screening differentially expressed genes in MDS. The relationship between miR-144 and A-kinase anchoring protein 12 (AKAP12) was determined by a dual luciferase reporter gene assay. Subsequently, gain- and loss-function approaches were used to assess the effects of miR-144 and AKAP12 on cell proliferation, cell cycle and cell apoptosis by MTT assay and flow cytometry. Following the induction of a mouse model with MDS, the tumor tissues were extract for evaluation of apoptosis and the expression of miR-144, AKAP12, and the relevant genes associated with extracellular-regulated protein kinases 1/2 (ERK1/2) signaling pathway and apoptosis. We observed significantly diminished expression of AKAP12 in MDS samples. miR-144 directly bound to AKAP12 3'UTR and reduced its expression in hematopoietic cells. Downregulation of miR-144 or upregulation of AKAP12 was observed to prolong cell cycle, inhibit cell proliferation, and induce apoptosis, accompanied by increased expression of AKAP12, p-ERK1/2, caspase-3, caspase-9, Bax, and p53, as well as decreased expression of Bcl-2. The transplanted tumors in mice with down-regulated miR-144 exhibited a lower mean tumor diameter and weight, and increased apoptosis index and expression of AKAP12 and ERK1/2. Taken together, these studies demonstrate the stimulative role of miR-144 in MDS progression by regulating AKAP12-dependent ERK1/2 signaling pathway. | Counterfeit |
We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases. | Authentic |
Parkinson's disease (PD) is a prevalent disease that leads to motor and cognitive disabilities, and oxidative stress (OS) injury was found to be related to the etiology of PD. Increasing evidence has shown that SHC3 is aberrantly expressed in neurons. The current study examines the involvement of SHC3 silencing in OS injury in the nigral dopamine neurons in rats with PD via the PI3K-AKT-FoxO signaling pathway. To study the mechanisms and functions of SHC3 silencing in PD at the tissue level, 170 rats were selected, and a lentivirus-based packaging system was designed to silence SHC3 expression in rats. Furthermore, PC12 cells were selected for in vitro experimentation. To evaluate the effect of SHC3 silencing in nigral dopamine neuronal growth, an MTT assay, propidium iodide (PI) single staining and Annexin V-PI double staining were performed to detect cell viability, cell cycle progression and cell apoptosis, respectively. SHC3 shRNA led to decreased SOD and MDA levels and enhanced GSH activity, indicating that SHC3 silencing leads to motor retardation. SHC3 silencing repressed the extent of Akt and FoxO phosphorylation, thereby inhibiting the PI3K-AKT-FoxO signaling pathway. Furthermore, in cell experiments, SHC3 silencing suppressed PC12 cell proliferation and cell cycle progression, whereas it enhanced cell apoptosis. The current study provides evidence suggesting that SHC3 silencing may aggravate OS injury in nigral dopamine neurons via downregulation of the PI3K-AKT-FoxO signaling pathway in PD rats. | Counterfeit |
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption. | Authentic |
PCA3 and TMPRSS2-ERG are commonly overexpressed biomarkers in prostate cancer, but reports have emerged demonstrating altered expression also in areas outside the tumour foci in cancerous prostates. Our aim was to measure PCA3 and TMPRSS2-ERG expression systematically in all regions of prostate cross-sections, matching the data to corresponding tissue morphology. TMPRSS2-ERG and PCA3 mRNA levels were measured with quantitative reverse-transcription PCR assays in 270 samples from cross-sections of five radical prostatectomy specimens. ERG expression was examined by immunohistochemistry. TMPRSS2-ERG mRNAs were detected in three patients and in 15 tissue samples in total. These included two carcinoma samples and 13 histologically benign samples, eight of which were located next to malignant tumours or PIN (prostatic intraepithelial neoplasia) lesions and five of which did not reside in the vicinity of any evident carcinoma foci. ERG protein expression was limited to areas of TMPRSS2-ERG mRNA expression, but did not identify all of them. PCA3 expression was detected in all five cross-sections, with statistically significant, three-fold higher expression in carcinoma regions. TMPRSS2-ERG expression was detected in carcinoma foci, regions next to them, and in samples not adjacent to carcinoma foci. Claimed as a cancer-associated phenomenon, this fusion gene measurement could, if validated with a larger cohort, be utilized as an addition to histological analysis to predict current or future cancer risk in men with negative biopsies. Molecular changes outside the carcinoma foci are also indicated for PCA3, as its expression was only moderately increased in the carcinoma regions. | Authentic |
microRNAs (miRNAs) have been revealed to participate in the pathological process of atherosclerosis (AS). However, the exact role of miR-338-3p, a target miRNA of BMP and activin membrane-bound inhibitor (BAMBI), and its possible molecular mechanism in AS remain unidentified. In this study, we found that BAMBI was significantly decreased, whereas miR-338-3p increased in patients with AS and oxidized low-density lipoprotein (ox-LDL)-induced HUVEC cells. Furthermore, overexpression of miR-338-3p significantly decreased cell viability and elevated cell apoptosis, whereas its inhibition significantly promoted cell viability and inhibited cell apoptosis in ox-LDL-induced HUVEC cells. Moreover, miR-338-3p overexpression increased TGF-β/Smad pathway activation in ox-LDL-induced HUVEC cells. A dual-luciferase reporter assay confirmed the direct interaction between miR-338-3p and the 3'-untranslated region of BAMBI messenger RNA. Furthermore, the suppression of BAMBI ameliorated the effect of miR-338-3p inhibition against ox-LDL-induced HUVEC cell injury. In conclusion, our study thus suggests that miR-338-3p promoted ox-LDL-induced HUVEC cell injury by targeting BAMBI and activating the TGF-β/Smad pathway, which may provide a novel and promising therapeutic target for AS. | Counterfeit |
microRNAs (miRNAs) have been reported to regulate proliferation and migration by down-regulating the expression of target genes. The aims of this study were to investigate whether miR-4316 inhibited proliferation and migration by downregulating vascular endothelial growth factor A (VEGF-A) and its clinical significance in gastric cancer (GC). The clinical tissues of the GC patients for miR-4316 and VEGF-A were detected by qRT-PCR. The protein levels of VEGF-A and c-Met were determined by western blotting. Cell Proliferation, migration, and colony forming assays were conducted to show whether miR-4316 affects proliferation by CCK-8, migration by transwell, wound healing and colony formation assays. The bioinformatic methods and luciferase reporter assay were applied to detect the relationship between miRNA and VEGF-A on its targeting 3-untranslated regions (3-UTRs). CCK-8, colony formation, wound healing, and transwell assay were performed to explore the function of miR-4316. The results of qRT-PCR indicated that miR-4316 expression level was significantly downregulated in human GC tissues and GC cell lines compared with their control. miR-4316 inhibited proliferation, migration and colony formation in GC cell lines by reducing VEGF-A. And western blot results indicated that miR-4316 significantly inhibited GC through repressing VEGF-A and c-Met. The investigation of Luciferase assay indicated that VEGF-A is a direct target gene of miR-4316. miR-4316 suppressed proliferation and migration of GC through the VEGF-A gene. MiR-4316 acts as a tumor suppressor by targeting VEGF-A and this indicated that MiR-4316 might be a potential therapeutic target for GC. | Counterfeit |
Apoptosis, the major form of programmed cell death in metazoan organisms, plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation contributes to many pathological states, including cancer, autoimmunity, infection and degenerative disorders. In vertebrates, it can be triggered either by engagement of 'death receptors' of the tumour necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the Bcl-2 protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both pathways lead to cellular demolition by dedicated proteases termed caspases. This review discusses the groundbreaking experiments from many laboratories that have clarified cell death regulation and galvanised efforts to translate this knowledge into novel therapeutic strategies for the treatment of malignant and perhaps certain autoimmune and infectious diseases. | Authentic |
Gastric cancer (GC) is one of the most common tumors and the molecular mechanism underlying its metastasis is still largely unclear. Here, we show that miR-25 was overexpressed in plasma and primary tumor tissues of GC patients with tumor node metastasis stage (III or IV) or lymph node metastasis. MiR-25 inhibition significantly decreased the metastasis, invasion and proliferation of GC cells in vitro, and reduced their capacity to develop distal pulmonary metastases and peritoneal dissemination in vivo. Furthermore, miR-25 repressed transducer of ERBB2, 1 (TOB1) expression by directly binding to TOB1-3'-UTR, and the inverse correlation was observed between the expressions of miR-25 and TOB1 mRNA in primary GC tissues. Moreover, the loss of TOB1 increased the metastasis, invasion and proliferation of GC cells, and the restoration of TOB1 led to suppressed metastasis, invasion and proliferation. The receiver operating characteristics analysis yielded an area under the curve value of 0.7325 in distinguishing the GC patients with death from those with survival. The analysis of optimal cutoff value revealed poor survival in GC patients with high plasma concentrations of miR-25 (>0.2333 amol/μl). Taken together, miR-25 promotes GC progression by directly downregulating TOB1 expression, and may be a noninvasive biomarker for the prognosis of GC patients. | Counterfeit |
Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. | Authentic |
To study the risk of incident breast cancer and subtype-specific breast cancer in relation to excess body weight in a contemporary Swedish prospective cohort study, The Karolinska Mammography Project for Risk Prediction of Breast Cancer, KARMA. A total of 35,412 postmenopausal women attending mammography and included in the KARMA study provided baseline data on body mass index (BMI) and potential confounders. During eight years of follow-up, 822 incident invasive breast cancer cases were identified. Women with overweight (BMI ≥ 25-< 30 kg/m2) constituting 34% of the study cohort had an increased risk of incident breast cancer with an adjusted Hazard Ratio (HRadj) 1.19 (95% CI 1.01-1.4). A similar, however, non-significant, association was found for women with obesity (BMI ≥ 30 kg/m2) conferring 13% of the cohort, with a HRadj of 1.19 (95% CI 0.94-1.5). Overweight was associated with risk of node-negative disease (HRadj 1.29, 95% CI 1.06-1.58), whereas obesity was associated with node-positive disease (HRadj 1.64, 95% CI 1.09-2.48). Both overweight and obesity were associated with risk of estrogen receptor positive (ER+) disease (HRadj 1.20, 95% CI 1.00-1.44 and HRadj 1.33, 95% CI 1.03-1.71, respectively), and low-grade tumors (HRadj 1.25, 95% CI 1.02-1.54, and HRadj 1.40, 95% CI 1.05-1.86, respectively). Finally, obesity was associated with ER+HER2 negative disease (HRadj 1.37, 95% CI 1.05-1.78) and similarly luminal A tumors (HRadj 1.43, 95% CI 1.02-2.01). Overweight and obesity are associated with an increased risk of developing breast cancer, specifically ER+, low-grade, and for obesity, node-positive, high-risk breast cancer indicating a further need for risk communication and preventive programs. | Authentic |
Background: Several studies have reported increased incidence trends of malignant gliomas in the late 1900s with a plateau in the 2000s, but also some recent increases have been reported. The purpose of our study was to analyze incidence trends of malignant gliomas in Finland by morphology and tumor location. Material and methods: Data on 4730 malignant glioma patients were obtained from case notifications to the nationwide, population-based Finnish Cancer Registry (FCR), and less detailed data on 3590 patients up to 2016. Age-standardized incidence rates (ASR) and average annual percent changes (APCs) in the incidence rates were calculated by histological subtype and tumor location. Results: The incidence rate of gliomas was 7.7/100,000 in 1990-2006 and 7.3 in 2007-2016. The incidence of all gliomas combined was stable during both study periods, with no departure from linearity. In an analysis by age group, increasing incidence was found only for ages 80 years and older (1990-2006). During both study periods, incidence rates were increasing in glioblastoma and decreasing in unspecified brain tumors. In 1990-2006, rates were also increasing for anaplastic oligodendroglioma, oligoastrocytoma and unspecified malignant glioma, while decreasing for astrocytoma. As for tumor location, incidence in 1990-2006 was increasing for frontal lobe and brainstem tumors, as well as those with an unspecified location, but decreasing for the parietal lobes, cerebrum and ventricles. Conclusions: No increasing incidence trend was observed for malignant gliomas overall. An increasing incidence trend of malignant gliomas was found in the oldest age group during 1990-2006. | Authentic |
Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients. | Authentic |
This study aimed to investigate the effect and potential modulation mechanism of lnc-SLC4A1-1 on breast cancer (BC) carcinogenesis. The expression of lnc-SLC4A1-1 in tissue and serum samples from BC patients, as well as BC cell lines, was detected by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Next, the expression of lnc-SLC4A1-1 was silenced or upregulated in BC cells, then cell proliferation, apoptosis, migration and invasion were detected using MTT, flow cytometry analysis and Transwell assay. Meanwhile, the expression of apoptosis-related proteins and epithelial-mesenchymal transition-related proteins were detected by western blotting. Furthermore, potential mechanism of lnc-SLC4A1-1 was explored by chromatin immunoprecipitation and RNA immunoprecipitation assays. CXCL8 was overexpressed to evaluate the relationship between lnc-SLC4A1-1 and CXCL8. Lnc-SLC4A1-1 was significantly up-regulated in BC tissue, serum samples and cell lines. In BC cells, lnc-SLC4A1-1 knockdown promoted cell apoptosis and suppressed cell proliferation, migration and invasion. Furthermore, lnc-SLC4A1-1 is transcriptionally activated by H3K27 acetylation, and lnc-SLC4A1-1 interacted with transcription factor (NF)-κB p65, thereby regulating CXCL8 expression. Meanwhile, CXCL8 overexpression partly reversed the effects of lnc-SLC4A1-1 knockdown on cell viability, apoptosis, migration and invasion in BC cells. Lnc-SLC4A1-1 could promote the development of BC by regulating NF-κB/CXCL8. Highlights Lnc-SLC4A1-1 was overexpressed in BC tissues, blood and cell lines. Lnc-SLC4A1-1 was transcriptionally activated by H3K27 acetylation. Lnc-SLC4A1-1 interacted with NF-κB to promote CXCL8 expression. Lnc-SLC4A1-1 could promote the development of BC. | Counterfeit |
Helicobacter pylori (H. pylori) has been shown to be a causal factor of gastric cancer in cohort studies and animal models. Meta-analysis of case-control studies nested within prospective cohorts showed that H. pylori infection was associated with a 5.9-fold increased risk of non-cardia gastric cancer. Prospective cohort studies showed that gastric cancer developed in 1-4% of H. pylori-infected subjects. Gastric cancer was successfully induced in Mongolian gerbils and insulin-gastrin (INS-GAS) transgenic mice after inoculation of H. pylori. Meta-analysis of randomized control trials also showed that eradication of H. pylori may reduce the risk of gastric cancer. However, there are several concerns regarding the widespread use of antibiotics to prevent gastric cancer, including the emergence of antibiotic resistance and the perturbation of gut microbiota after H. pylori eradication. Recent studies showed that eradication of H. pylori resulted in an increase in the bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to H. pylori non-infected subjects in the gastric microbiota. The administration of antibiotics may also alter the composition of intestinal microbiota. The α-diversity and β-diversity of fecal microbiota are significantly altered immediately after H. pylori eradication but are gradually restored to levels similar to those before therapy. Yet, the rate of recovery varies with regimens. The diversity was restored at week 8 after triple therapy but was not yet fully recovered at 1 year after concomitant and quadruple therapies. Some studies showed that supplementation of probiotics may reduce the dysbiosis during H. pylori eradication therapy. Although some earlier studies showed high levels of macrolide resistance after triple therapy, recent studies showed that the increased antibiotic resistance rate may be restored 2-12 months after eradication therapy. These results collectively provide evidence of the long-term safety of H. pylori eradication. Yet, more prospective cohort studies and randomized trials are warranted to assess the efficacy and long-term safety of H. pylori eradication for gastric cancer prevention. | Authentic |
Dandelion (Taraxacum species) is a wild plant with over 2500 species. Flavonoids, phenolic compounds, saponins, sesquiterpenes, and sugars have been detected in the organs of Taraxacum, and for centuries it has been used in traditional medicine for the relief and treatment of various diseases. However, details of its working mechanism remain unclear. Bioactive compounds in herbal extracts generally have low yields, which makes their isolation and purification intensive in terms of time and cost. Here, to assess their versatility and safety, we applied aqueous extracts of two species of Taraxacum, T. mongolicum and T. formosanum, including extracts of both fresh and dried T. formosanum, to compare their potential antitumor effects on HeLa human cervical cancer cells, three liver cancer cell lines, and one normal liver cell line. After being treated with a lower dose of Taraxacum, the upregulation of subG1 and S populations, as well as increased levels of p-eIF2[Formula: see text]-to-eIF2[Formula: see text] ratio, were observed in HeLa cells, whereas the downregulation of S population and the absence of mRNA expressions were detected in HeLa cells when being treated with a higher dose of Taraxacum. These results indicated that Taraxacumcould induce apoptosis and endoplasmic reticulum stress while suppressing proliferation, transcription, colony formation, migration, and invasion. What's more, we also found that the effects of fresh T. formosanum were much stronger than that of T. mongolicumin HeLa cells. Based on these results, we suggest that T. formosanum may contain specific compound(s) that are potentially useful for cancer therapy. However, much work remains to identify these effective compounds for the future application of Taraxacumto cancer therapy. | Authentic |
Accumulating evidence has demonstrated that aberrant miRNAs contribute to cervical cancer (CC) development and progression. However, the roles of various miRNAs in CC remain to be determined. In the present study, we confirmed that a decreased miR-1297 expression was present in CC tissues and cell lines. Our clinical analysis revealed that the downregulated miR-1297 expression was significantly correlated with poor prognostic features including lymph node metastasis and lymphovascular space invasion. Moreover, we confirmed that miR-1297 was a novel independent prognostic marker for predicting the 5-year survival of CC patients. The ectopic overexpression of miR-1297 inhibited cell migration, invasion and EMT progression, while downregulated miR-1297 reversed these effects. In addition, miR-1297 regulated AEG-1 by directly binding to its 3'-UTR. In clinical samples of CC, miR-1297 was inversely correlated with AEG-1, which was upregulated in CC. Alteration of AEG-1 expression at least partially abolished the migration, invasion and EMT progression effects of miR-1297 on CC cells. In conclusion, our results indicated that miR-1297 functioned as a tumor suppressor gene in regulating the EMT and metastasis of CC via targeting of AEG-1, and may represent a novel potential therapeutic target and prognostic marker for CC. | Counterfeit |
Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer. | Authentic |
Adaptive chemoresistance and consequent tumor recurrence present major obstacles to the improvement of the prognosis and quality-of-life of patients with advanced-stage ovarian cancer. In this issue of Cancer Cell, Yu and colleagues describe the critical role of spleen tyrosine kinase (SYK) in paclitaxel resistance by modulating the stability of microtubules. | Authentic |
Real-world predictors of the treatment efficacy of immune checkpoint inhibitors for hepatocellular carcinoma (HCC) are unknown. This retrospective study enrolled 87 consecutive patients with unresectable HCC from May 2017 to December 2019 at two hospitals. Of the 87 patients, 7, 9, 60, and 11 patients had Barcelona Clinic Liver Cancer stages A, B, C, and D, respectively, and 45, 30, and 10 patients were Child-Pugh class A, B, and C, respectively. The median injection numbers of nivolumab and treatment duration were 6 (3-8) and 2.53 (1.47-4.23) months, respectively, and 64.4% of patients received combination therapy. Radiological imaging was not assessed for 25 patients. Objective response (OR) and disease control rates were 19.5% and 39.1%, respectively. A single tumor (odds ratio: 9.542, P = .015) and ≥20% decline in serum α-fetoprotein protein (AFP) levels within the first 3 months of treatment (defined as AFP response, odds ratio: 5.997, P = .042) were predictors of OR. Lack of macrovascular invasion, combination therapy, and AFP response were predictors of progression-free survival. A Cancer of the Liver Italian Program (CLIP) score of 0-2 (hazard ratio [HR]: 3.717, P = .004) and grade 1-2 immune-related adverse events (irAEs, HR: 2.217, P = .049) were predictors of overall survival (OS) in the entire cohort, and a CLIP score of 0-2 (HR: 3.257, P = .009) was a predictor of OS in evaluable patients. IrAEs ≥ grade 3 were noted in 14 patients, and three died as a result. Having a single tumor and AFP response were predictors of OR, and CLIP score was a predictor of OS. | Authentic |
Gastric cancer (GC) is one of the most common malignancies worldwide manifesting high morbidity and mortality. Cancer-associated fibroblasts (CAFs), important components of the tumor microenvironment, are essential for tumorigenesis and progression. Exosomes secreted from CAFs have been reported as the critical molecule-vehicle in intercellular crosstalk. However, the precise mechanism underlying the effect of CAFs remains to be fully investigated. In this study, we aimed to determine the role of CAFs and their exosomes in the progression of GC and related mechanisms. The results revealed that miRNA-34 was downregulated in both GC fibroblasts (GCFs) and GC cell lines while the overexpression of miRNA-34 suppressed the proliferation, invasion, and motility of GC cell lines. Coculturing GC cells with miRNA-34-overexpressing GCFs led to the suppression of cancer progression. Also, exosomes derived from GCFs were taken up by GC cells in vitro and in vivo and exerted antitumor roles in GC. In addition, exosomal miRNA-34 inhibited GC cell proliferation and invasion in vitro and suppressed tumor growth in vivo. Furthermore, 16 genes were identified as potential downstream targeting genes of miRNA-34. Taken together, GCFs-derived exosomal miRNA-34 may be a promising targeting molecule for therapeutic strategies in GC. | Counterfeit |
Stroke is common in cancer patients, but risk estimates for different cancer sites/types have not been determined. The aim of this nationwide study was to examine whether there is an association between cancer and first hospitalisation for haemorrhagic or ischaemic stroke. All 820,491 individuals in Sweden with a diagnosis of cancer between 1st January 1987 and 31st December 2008 were followed for first hospitalisation for haemorrhagic or ischaemic stroke. The reference population was the total population of Sweden without cancer. Standardised incidence ratios (SIRs) for haemorrhagic and ischaemic strokes were calculated. Overall risk of haemorrhagic stroke and ischaemic stroke during the first 6 months after diagnosis of cancer was 2.2 (95% confidence interval (CI)= 2.0-2.3) and 1.6 (CI = 1.5-1.6), respectively. For 18 and 20 of the 34 cancers studied, respectively, risk of haemorrhagic and ischaemic strokes was increased. Overall stroke risk decreased rapidly, but remained elevated, even 10+years after diagnosis of cancer 1.2 (CI = 1.1-1.3) for haemorrhagic stroke and 1.1 (CI = 1.1-1.2) for ischaemic stroke. The risk of stroke was highest during the first 6 months after diagnosis of cancer of the nervous system (29 (CI = 25-34) for haemorrhagic stroke and 4.1 (CI = 3.4-4.8) for ischaemic stroke)) or leukaemia (13 (CI = 10-16) for haemorrhagic stroke and 3.0 (CI = 2.5-3.7) for ischaemic stroke)). Metastasis was associated with an increased risk of haemorrhagic stroke 2.2 (CI = 1.8-2.7) and ischaemic stroke 1.5 (CI = 1.3-1.7). Several cancer sites/types are associated with an increased risk of haemorrhagic and ischaemic strokes. | Authentic |
Oral cancer being one of the lethal cancers is generally detected at advanced stages and causes significant mortality world over. The unavailability of the reliable biomarkers and therapeutic targets/agents forms a bottleneck in the treatment of oral cancer. MicroRNAs are considered of immense therapeutic potential for the treatment of cancer. Consistently, in this study the role and therapeutic potential of miR-650 was explored in oral cancer. The analysis of miR-650 expression by qRT-PCR revealed significant (p < 0.05) upregulation of miR-650 in oral cancer cell lines. Cell cycle analysis by flow cytometery revealed that suppression of miR-650 significantly (p < 0.05) inhibits the proliferation of the SCC-25 cells by prompting Sub-G1 cell cycle arrest. Further, miR-650 suppression also inhibited the migration and invasion of the SCC-25 oral cancer cells as revealed by transwell assays. TargetScan analysis showed that miR-650 targets Growth factor independent 1 (Gfi1). Moreover, the results of western blot analysis showed that miR-650 suppression inhibits the expression of Gfi1. Interestingly, suppression of Gfi1 exhibited similar effects on cell proliferation, migration and invasion of the oral cancer cells as that of miR-650 suppression. Nonetheless, miR-650 promoted the proliferation, migration and invasion of the SCC-25 cells by upregulating the expression of Gfi1. Moreover, overexpression of miR-650 could not rescue the effects of Gfi1 silencing on SCC-25 oral cancer cells. Conversely, overexpression of Gfi1 could rescue the effects of miR-650 inhibition on SCC-25 cell proliferation, migration and invasion. Additionally, miR-650 suppression could also inhibit the xenografted tumor growth in vivo by inhibiting the expression of Gfi1. Taken together, miR-650 may prove to be an important therapeutic target for the management of oral cancers. | Counterfeit |
Shikonin, a naphthoquinone pigment isolated from the Chinese herbal Zicao, has been shown to exhibit antioxidant and anticancer effects. In the present study, we investigated the antiproliferative and pro-apoptotic effects of shikonin on A431 cells and explored the underlying molecular mechanisms. In the present study, our results showed that shikonin significantly inhibited the growth of A431 cells in a concentration- and time-dependent manner, and caused cell cycle arrest by upregulation of p21 and p27, and downregulation of cyclins and cyclin-dependent kinases. In addition, shikonin evidently induced apoptosis due to decreasing Bcl-2 expression, increasing Bax expression, activating caspase and inactivating NF-κB, while pretreatment with a pan-caspase inhibitor Z-Asp-CH2-DCB abrogated shikonin-induced apoptosis. Moreover, EGF could significantly increase the NF-κB DNA-binding activity and reversed the shikonin-induced inactivation of NF-κB. As anticipated AG1478 (EGFR inhibitor) and Bay11-7082 (NF-κB inhibitor) blocked EGF-reversed the inactivation of NF-κB induced by shikonin. Our data also showed that EGF could evidently reverse the shikonin-induced decreases in cell viability and increases in apoptosis. Then, the NF-κB inhibitors such as Bay11-7082, SN50, Helenalin and the EGFR inhibitor AG1478 and its downstream inhibitor such as PI3K inhibitor LY294002 and STAT3 inhibitor Stattic dramatically blocked EGF-reversed decreases in cell viability and increases in apoptosis induced by shikonin. Collectively, our findings indicated that shikonin inhibited cell growth and caused cell cycle arrest of the A431 cells through the regulation of apoptosis. Moreover, these effects were mediated at least partially by suppressing the activation of the EGFR-NF-κB signaling pathways. | Counterfeit |
Prostate cancer is one of the most ordinary malignant tumors. Recently, the role of long non-coding RNAs (lncRNAs) in tumor progression has caught the attention of numerous researchers. In this work, lncRNA SNHG14 was studied to identify how it functioned in the progression of prostate cancer. First, Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to measure SNHG14 expression in prostate cancer tissues and cell lines. Furthermore, to identify the function of SNHG14 in prostate cancer, functional experiments were conducted in vitro and in vivo. In addition, by performing Luciferase assays and RNA immunoprecipitation assay (RIP), the underlying mechanism was explored. In this work, SNHG14 expression was remarkably higher in prostate cancer samples when compared with that in the corresponding ones. Moreover, cell proliferation was inhibited after SNHG14 was silenced in prostate cancer cells and the expression of miR-613 was upregulated after SNHG14 was silenced. Further mechanism assays showed that miR-613 was a direct target of SNHG14 in prostate cancer. In addition, tumor formation was inhibited after SNHG14 was knocked-down in vivo. Our study discovers a potential oncogene in prostate cancer and identifies that SNHG14 enhances cell proliferation via sponging miR-613. | Counterfeit |
Cancer immunotherapy often depends on recognition of peptide epitopes by cytotoxic T lymphocytes (CTLs). The tumor microenvironment (TME) is enriched for peroxynitrite (PNT), a potent oxidant produced by infiltrating myeloid cells and some tumor cells. We demonstrate that PNT alters the profile of MHC class I bound peptides presented on tumor cells. Only CTLs specific for PNT-resistant peptides have a strong antitumor effect in vivo, whereas CTLs specific for PNT-sensitive peptides are not effective. Therapeutic targeting of PNT in mice reduces resistance of tumor cells to CTLs. Melanoma patients with low PNT activity in their tumors demonstrate a better clinical response to immunotherapy than patients with high PNT activity. Our data suggest that intratumoral PNT activity should be considered for the design of neoantigen-based therapy and also may be an important immunotherapeutic target. | Authentic |
Plantaginaceae, a popular traditional Chinese medicine, has long been used for treating various diseases from common cold to cancer. Linalool is one of the biologically active compounds that can be isolated from Plantaginaceae. Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible tumor cells. However, the signaling pathway for apoptosis remains undefined. In this study, the cytotoxic effect of linalool on human cancer cell lines was investigated. Water-soluble tetrazolium salts (WST-1) based colorimetric cellular cytotoxicity assay, was used to test the cytotoxic ability of linalool against U937 and HeLa cells, and flow cytometry (FCM) and genechip analysis were used to investigate the possible mechanism of apoptosis. These results demonstrated that linalool exhibited a good cytotoxic effect on U937 and HeLa cells, with the IC50 value of 2.59 and 11.02 μM, respectively, compared with 5-FU with values of 4.86 and 12.31 μM, respectively. After treating U937 cells with linalool for 6 h, we found an increased sub-G1 peak and a dose-dependent phenomenon, whereby these cells were arrested at the G0/G1 phase. Furthermore, by using genechip analysis, we observed that linalool can promote p53, p21, p27, p16, and p18 gene expression. Therefore, this study verified that linalool can arrest the cell cycle of U937 cells at the G0/G1 phase and can arrest the cell cycle of HeLa cells at the G2/M phase. Its mechanism facilitates the expression of the cyclin-dependent kinases inhibitors (CDKIs) p53, p21, p27, p16, and p18, as well as the non-expression of cyclin-dependent kinases (CDKs) activity. | Authentic |
Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia. | Counterfeit |
Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Studies have confirmed an association between microRNA (miRNA) and the BRAFV600E mutation in various cellular biological processes of PTC. This study aimed to clarify the potential relationship between miR-150-5p and the BRAFV600E mutation in PTC. Human PTC cell lines B-CPAP and TPC-1 were transfected with the miR-150-5p mimic, an inhibitor, and the corresponding controls. Then, cell proliferation, viability, and apoptosis were detected by bromodeoxyuridine, trypan blue exclusion, and flow cytometry assays. The expressions of the main factors of cell cycle, epithelial mesenchymal transition (EMT), and DNA mismatch repair were examined by Western blot analysis and a real-time quantitative polymerase chain reaction. Additionally, pc-BRAFV600E was transfected into B-CPAP and TPC-1 cells to determine the relationship between miR-150-5p and BRAFV600E . In addition, the methyl ethyl ketone (MEK)/extracellular signal-regulated kinase (ERK) signal pathway was examined using Western blot analysis. Overexpression of miR-150-5p promoted cell proliferation and viability, inhibited apoptosis, and upregulated cell cycle factor expressions at 50 passages of B-CPAP and TPC-1 cells after transfection. Overexpression of miR-150-5p led to an obvious decrease in E-cadherin expression, but enhanced N-cadherin, Slug and Vimentin, ZEB1, and Snail expression. Moreover, overexpression of miR-150-5p markedly suppressed POLD3, MSH2, and MSH3 expression. Furthermore, BRAFV600E overexpression increased the expression level of miR-150-5p in TPC cells, and overexpression of telomerase reverse transcriptase further enhanced the promoting effect of BRAFV600E on miR-150-5p expression in B-CPAP and TPC-1 cells. Finally, BRAFV600E overexpression activated the MEK/ERK signal pathway in B-CPAP and TPC-1 cells. These data indicated that miR-150-5p promoted cell proliferation, suppressed apoptosis, and accelerated the EMT process by regulation of the BRAFV600E mutation. Our findings will help elucidate the pathogenesis of PTC and identify biomarkers. | Counterfeit |